US20040006081A1 - Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity - Google Patents

Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity Download PDF

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US20040006081A1
US20040006081A1 US10/276,430 US27643002A US2004006081A1 US 20040006081 A1 US20040006081 A1 US 20040006081A1 US 27643002 A US27643002 A US 27643002A US 2004006081 A1 US2004006081 A1 US 2004006081A1
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alkyl
heteroaryl
phenyl
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Jeremy Burrows
Anne Cooper
John Cumming
Thomas McInally
Howard Tucker
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AstraZeneca AB
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Assigned to ASTRAZENECA AB reassignment ASTRAZENECA AB ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BURROWS, JEREMY, CUMMING, JOHN, TUCKER, HOWARD, COOPER, ANNE, MCLNALLY, THOMAS
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents.
  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a consideration in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif.
  • the chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or ⁇ ) and Cys-Cys (C-C, or ⁇ ) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
  • the C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
  • IL-8 interleukin-8
  • NAP-2 neutrophil-activating peptide 2
  • the C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1 ⁇ and 1 ⁇ (MIP-1 ⁇ and MIP-1 ⁇ ).
  • chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • G protein-coupled receptors among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4.
  • the CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally “regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MIP-1a and MIP-1b and monocyte chemoattractant protein-2 (MCP-2).
  • RANTES normal T-cell expressed and secreted
  • MIP macrophage inflammatory proteins
  • MIP-1a and MIP-1b monocyte chemoattractant protein-2
  • CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection.
  • the present invention provides a compound of formula (I):
  • R 1 is C 1-6 alkyl, C 3-7 cycloalkyl, C 3-8 alkenyl or C 3-8 alkynyl, each optionally substituted with one or more of: halo, hydroxy, cyano, nitro, C 3-7 cycloalkyl, NR 8 R 9 , C(O)R 10 , NR 13 C(O)R 14 , C(O)NR 17 R 18 , NR 19 C(O)NR 20 R 21 , S(O) n R 22 , C 1-6 alkoxy (itself optionally substituted by heterocyclyl or C(O)NR 23 R 24 ), heterocyclyl, heterocyclyloxy, aryl, aryloxy, heteroaryl or heteroaryloxy;
  • R 2 is hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C 1-4 )alkyl, heteroaryl(C 1-4 )alkyl or heterocyclyl(C 1-4 )alkyl;
  • R 3 is C 1-8 alkyl, C 2-8 alkenyl, NR 45 R 46 , C 2-8 alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(C 1-4 )alkyl, heteroaryl(C 1-4 )alkyl or heterocyclyl(C 1-4 )alkyl;
  • R 46 is C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C 1-4 )alkyl, heteroaryl(C 1-4 )alkyl or heterocyclyl(C 1-4 )alkyl;
  • R 2 , R 3 and R 46 , and the heterocyclyl, aryl and heteroaryl moieties of R 1 are independently optionally substituted by one or more of halo, cyano, nitro, hydroxy, S(O) q R 25 , OC(O)NR 26 R 27 , NR 28 R 29 , NR 30 C(O)R 31 , NR 32 C(O)NR 33 R 34 , S(O) 2 NR 35 R 36 , NR 37 S(O) 2 R 38 , C(O)NR 39 R 40 , C(O)R 41 , CO 2 R 42 , NR 43 CO 2 R 44 , C 1-6 alkyl, C 3-10 cycloalkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, phenyl, phenyl(C 1-4 )alkyl, phenoxy, phenylthio, phenyl(
  • any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or OCF 3 ; the C 3-7 cycloalkyl, aryl, heteroaryl and heterocyclyl moieties of R 1 , R 2 and R 3 being additionally optionally substituted with C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or C 1-6 alkoxy(C 1-6 )alkyl;
  • R 4 , R 5 , R 6 and R 7 are, independently, hydrogen, C 1-6 alkyl ⁇ optionally substituted by halo, cyano, hydroxy, C 1-4 alkoxy, OCF 3 , NH 2 , NH(C 1-4 alkyl), N(C 1-4 alkyl) 2 , NHC(O)(C 1-4 alkyl), N(C 1-4 alkyl)C(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), N(C 1-4 alkyl)S(O) 2 (C 1-4 alkyl), CO 2 (C 1-4 alkyl), C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 , C(O)NH 2 , CO 2 H, S(O) 2 (C 1-4 alkyl), S(O) 2 NH(C 1-4 alkyl), S(O) 2 N(C 1-4 alkyl) 2 , heterocyclyl
  • X is C(O), S(O) 2 , C(O)C(O), a direct bond or C(O)C(O)NR 47 ;
  • k, m, n, p and q are, independently, 0, 1 or 2;
  • R 38 , R 39 , R 40 , R 41 , Re 42 , R 43 and R 44 are, independently, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC(O)NH 2 , C(O)NH 2 , NHC(O)CH 3 , S(O) 2 N(CH 3 ) 2 , S(O) 2 NHCH 3 , CF 3 , CHF 2 , CH 2 F, CH 2 CF 3 or OCF 3 ; and R 26 , R 27 , R 28 , R 29 , R 30 ,
  • R 8 , R 9 , R 10 , R 13 , R 14 , R 17 , R 18 , R 19 , R 20 , R 21 , R 23 , R 24 , R 45 and R 47 are, independently, hydrogen, alkyl ⁇ optionally substituted by halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C 1-4 alkyl or C 1-4 alkoxy) ⁇ , phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O
  • R 22 is alkyl ⁇ optionally substituted by halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C 1-4 alkyl or C 1-4 alkoxy) ⁇ , phenyl (itself optionally substituted by halo, hydroxy, cyano, C 1-4 alkyl or C 1-4 alkoxy) or heteroaryl (itself optionally substituted by halo, hydroxy, cyano, C 1-4 alkyl or C 1-4 alkoxy);
  • R 8 and R 9 , R 13 and R 14 , R 17 and R 18 , R 20 and R 21 , R 23 and R 24 , R 26 and R 27 , R 28 and R 29 , R 30 and R 31 , R 32 with either R 33 or R 34 , R 33 and R 34 , R 35 and R 36 , R 37 and R 38 , R 39 and R 40 and R 43 and R 44 may, independently, join to form a ring and such a ring may also comprise an oxygen, sulphur or nitrogen atom;
  • —N(H)— moiety may be optionally substituted by C 1-4 alkyl (itself optionally substituted by hydroxy), C(O)(C 1-4 alkyl), C(O)NH(C 1-4 alkyl), C(O)N(C 1-4 alkyl) 2 or S(O) 2 (C 1-4 alkyl);
  • a ring nitrogen and/or sulphur atom is optionally oxidised to form an N-oxide and/or an S-oxide;
  • heteroaryl or heterocyclyl rings are C- or, where possible, N-linked;
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers).
  • the present invention covers all such isomers and mixtures thereof in all proportions.
  • Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
  • the compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates.
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl or iso-propyl.
  • Alkenyl and alkynyl groups and moieties are, for example, vinyl, allyl or propargyl.
  • Cycloalkyl is a mono-, bi- or tri-cyclic structure such as, for example, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl.
  • Cycloalkenyl comprises one double bond and is, for example, cyclopentenyl or cyclohexenyl.
  • Acyl is, for example, carbonyl substituted by either C 1-6 alkyl or optionally substituted phenyl.
  • Heterocyclyl is a non-aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.
  • Heterocyclyl is, for example, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or tetrahydrofuryl.
  • Heteroaryl is an aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur.
  • Heteroaryl is, for example, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, indolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl, phthalazinyl, indanyl, oxadiazolyl or benzthiazolyl.
  • Aryl is a carbocyclic aromatic ring system (for example phenyl or naphthyl).
  • Arylalkyl is, for example, benzyl, 1-(phenyl)ethyl or 2-(phenyl)ethyl.
  • Heteroarylalkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 2-(pyridinyl)ethyl.
  • the ring is, for example, a piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl ring.
  • the invention provides a compound of formula (I) wherein X is C(O), S(O) 2 or a direct bond. In a further aspect X is C(O).
  • the invention provides a compound of formula (I) wherein m and p are both 1.
  • the invention provides a compound of formula (I) wherein R 4 , R 5 , R 6 and R 7 are all hydrogen.
  • the invention provides a compound of formula (I) wherein R 2 is hydrogen, C 1-4 alkyl (optionally substituted by C 3-6 cycloalkyl or phenyl), C 3-4 alkenyl or C 3-4 alkynyl.
  • R 2 is hydrogen.
  • the invention provides a compound of formula (I) wherein R 2 is methyl, ethyl, allyl, cyclopropyl or propargyl.
  • the invention provides a compound of formula (I) wherein R 2 is methyl, ethyl or allyl.
  • the invention provides a compound of formula (I) wherein R 2 is C 3-8 alkenyl (such as allyl) or C 3-7 cycloalkyl (such as cyclopropyl).
  • X is C(O).
  • R 3 is NR 45 R 46 , aryl, heteroaryl, aryl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl;
  • R 45 is hydrogen or C 1-6 alkyl;
  • R 46 is aryl, heteroaryl, aryl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl; wherein the aryl and heteroaryl groups of R 3 and R 46 are independently substituted by S(O) q R 25 , OC(O)NR 26 R 27 , NR 32 C(O)NR 33 R 34 or C(O)R 41 , and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy(C 1-6 )alkyl, S(O) q R 25 , OC(O)NR 26 R 27 , NR 28
  • any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or OCF 3 ; wherein q, ke, R 25 , R 26 , R 27 , R 28 , R 29 , R 30 , R 31 , R 32 , R 33 , R 34 , R 35 , R 36 , R 37 , R 38 , R 39 , R 40 , R 41 , R 42 , R 43 and R 44 are as defined above.
  • R 3 is NR 45 R 46 , phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl;
  • R 45 is hydrogen or C 1-6 alkyl;
  • R 46 is phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl; wherein the phenyl and heteroaryl groups of R 3 and R 46 are substituted by S(O) 2 R 25 , OC(O)NR 26 R 27 , NR 32 C(O)NR 33 R 34 or C(O)R 41 , and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy(C 1-6 )alkyl, S(O) 2 R 25 , OC(O)NR 26 R 27 ,
  • R 3 is NR 45 R 46 , phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl;
  • R 45 is hydrogen or C 1-6 alkyl;
  • R 46 is phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl; wherein the phenyl and heteroaryl groups of R 3 and R 46 are substituted by S(O) 2 R 25 , and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; wherein R 25 is C 1-6 alkyl.
  • R 3 is NR 45 R 46 , phenyl or phenylCH 2 ;
  • R 45 is hydrogen or C 1-2 alkyl;
  • R 46 is phenyl or phenylCH 2 ; wherein the phenyl groups of R 3 and R 46 are mono-substituted by S(O) 2 R 25 ; wherein R 25 is C 1-6 alkyl (for example methyl).
  • R 3 is phenyl or phenylCH 2 ; wherein the phenyl groups are mono-substituted (for example in the 4-position) by S(O) 2 R 25 ; wherein R 25 is C 1-6 alkyl (for example methyl).
  • R 3 is NR 45 R 46 , phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl;
  • R 45 is hydrogen or C 1-6 alkyl;
  • R 46 is phenyl, heteroaryl, phenyl(C 1-4 )alkyl or heteroaryl(C 1-4 )alkyl; wherein the phenyl and heteroaryl groups of R 3 and R 46 are substituted by S(O) 2 NR 35 R 36 , and optionally further substituted byone or more of halo, cyano, nitro, hydroxy, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy(C 1-6 )alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; wherein R 35 and R 36 are, independently, hydrogen, C 1-8 alkyl, C 3-8 alken
  • R 3 is NR 45 R 46 , phenyl or phenylCH 2 ;
  • R 45 is hydrogen or C 1-2 alkyl;
  • R 46 is phenyl or phenylCH 2 ; wherein the phenyl groups of R 3 and R 46 are mono-substituted by S(O) 2 NR 35 R 36 ; wherein R 35 and R 36 are, independently, hydrogen, C 1-8 alkyl, C 3-8 alkenyl, C 3-8 alkynyl, C 3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C 1-4 alkyl, C 1-4 alkoxy, SCH 3 , S(O)CH 3 , S(O) 2 CH 3 , NH 2 , NHCH 3 , N(CH 3 ) 2 , NHC(O)NH 2 , C(O)NH 2 , NHC(O)CH
  • the present invention provides a compound of formula (I) wherein X is C(O); and R 3 is C 3-7 cycloalkyl, (CH 2 ) 3 -aryl, (CH 2 ) 3 -heteroaryl, (CH 2 )aryl, (CH 2 )-heteroaryl, (CH 2 ) 3 C( ⁇ O)NH-aryl, (CH 2 ) 3 C( ⁇ O)NH-heteroaryl, (CH 2 )C 3-10 cycloalkyl, (CH 2 ) 5 NO 2 , (CH 2 ) 5 NC( ⁇ O)C 1-4 alkyl, CH 2 —CH ⁇ CH-aryl, CH 2 —CH ⁇ CH-heteroaryl, NH-aryl, NH-heterocyclyl, NH-allyl, NHCH 2 -aryl or NHCH 2 -heteroaryl; wherein aryl, heteroaryl and heterocyclyl groups are optionally substituted as defined
  • the present invention provides a compound of formula (I) wherein X is C(O); and R 3 is (CH 2 ) 3 -aryl, (CH 2 ) 3 -heteroaryl, (CH 2 )aryl, (CH 2 )-heteroaryl, (CH 2 ) 3 C( ⁇ O)NH-aryl, (CH 2 ) 3 C( ⁇ O)NH-heteroaryl, NH-aryl, NH-heterocyclyl, NHCH 2 -aryl or NHCH 2 -heteroaryl; wherein aryl, heteroaryl and heterocyclyl rings are optionally substituted as defined above.
  • the present invention provides a compound of formula (I) wherein X is C(O); and R 3 is CH 2 -phenyl (wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more substituents recited for aryl above), (CH 2 ) 3 -phenyl, (CH 2 ) 3 -oxadiazole-aryl, (CH 2 ) 3 -oxadiazole-heteroaryl, (CH 2 ) 3 C( ⁇ O)NH-phenyl, NHCH 2 -phenyl, NHCH 2 -heteroaryl or NH-phenyl (wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more substituents recited for aryl above); wherein aryl and heteroaryl rings are optionally substituted as defined above; phenyl rings are, unless stated otherwise, optionally substituted with one
  • the present invention provides a compound of formula (I) wherein X is C(O); and R 3 is CH 2 -phenyl [wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more of Cl, Br, F, OH, C 1-4 alkoxy (such as OMe or OEt), CN, S(O) 2 (C 1-4 alkyl) (such as S(O) 2 Me), S(O)(C 1-4 alkyl) (such as S(O)Me), S(C 1-4 alkyl) (such as SMe), S(O) 2 NH 2 , S(O) 2 N(C 1-4 alkyl) 2 (such as S(O) 2 NMe 2 ), C 1-4 alkyl (such as Me), CF 3 , OCF 3 , NO 2 , NHC(O)(C 1-4 alkyl) (such as NHCOMe), C(O)(C 1-4 alkyl) (such as NH
  • the present invention provides a compound of formula (I) wherein X is C(O); and R 3 is CH 2 -phenyl [wherein the phenyl ring is optionally substituted at the 4-position with Cl, Br, F, OH, OMe, CN, S(O) 2 Me, S(O) 2 NH 2 , S(O) 2 NMe 2 , CF 3 , OCF 3 , NO 2 , NHC(O)Me or CO 2 Me], NHCH 2 -phenyl [wherein the phenyl ring is optionally substituted at the 4-position with Cl, Me, F or OMe] or NH-phenyl [wherein the phenyl ring is optionally substituted at the 4-position with F, Cl, OMe or NMe 2 ).
  • the invention provides a compound as hereinbefore defined wherein R 1 is C 1-6 alkyl ⁇ optionally substituted by cyano, NR 13* C(O)R 14* , NR 15* R 16* , phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or OCF 3 ) or heteroaryl (itself optionally substituted by halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 ,
  • R 1 is a three-carbon chain which optionally carries one methyl group along its length (for example a methyl group is carried on the carbon that bonds to the nitrogen atom of the ring shown in formula (I)) wherein said three-carbon chain is optionally substituted as described for R 1 above.
  • the invention provides a compound as hereinbefore defined wherein R 1 is 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4-dimethoxy-6-hydroxybenzyl, 3-(4-dimethylamino-phenyl)prop-2-enyl, (1-phenyl-2,5-dimethylpyrrol-3-yl)methyl, 2-phenylethyl, 3-phenylpropyl, 3-R/S-phenylbutyl, 3-cyano-3,3-diphenylpropyl, 3-cyano-3-phenylpropyl, 4-(N-methylbenzamido)-3-phenylbutyl or 3,3-diphenylpropyl.
  • R 1 include each individual partial structure presented in Schedule I and each individual partial structure presented in Schedule I can be combined with any definition of X, R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , m or p as herein defined.
  • the invention provides a compound as hereinbefore defined wherein R 1 is 3-R/S-phenylbutyl or, preferably, 3,3-diphenylpropyl.
  • R 1 is 3-(S)-phenylbutyl.
  • R 1 is 3,3-diphenylpropyl.
  • the present invention provides a compound of formula (I) wherein R 1 is a hereinbefore defined; R 2 is ethyl, allyl or cyclopropyl (for example allyl or cyclopropyl); and R 3 is NHCH 2 C 6 H 5 , NHCH 2 (4-F—C 6 H 4 ), NHCH 2 (4-S(O) 2 CH 3 —C 6 H 4 ), NHCH 2 (4-S(O) 2 NH 2 —C 6 H 4 ), CH 2 C 6 H 5 , CH 2 (4-F—C 6 H 4 ), CH 2 (4-S(O) 2 CH 3 —C 6 H 4 ) or CH 2 (4-S(O) 2 NH 2 —C 6 H 4 ) ⁇ for example NHCH 2 (4-S(O) 2 CH 3 —C 6 H 4 ) or CH 2 (4-S(O) 2 CH 3 —C 6 H 4 ) ⁇ .
  • the present invention provides a compound of formula (I) wherein R 1 is 3,3-diphenylpropyl, X is CO, R 2 is C 1-8 alkyl, and R 3 is as hereinbefore defined.
  • the present invention provides a compound of formula (I) wherein R 1 is 3,3-diphenylpropyl, X is CO, R 2 is allyl, and R 3 is as hereinbefore defined.
  • the present invention provides a compound of formula (I) wherein R 1 is 3,3-diphenylpropyl or 3-R/S-phenylbutyl, X is C(O), R 2 is H, and R 3 is as hereinbefore defined.
  • the present invention provides a compound of formula (I) wherein R 1 is 3,3-diphenylpropyl or 3-R/S-phenylbutyl, X is C(O), R 2 is H or methyl, and R 3 is NR 45 R 46 (such as an amine group as hereinbefore defined for R 3 ).
  • R 14 is hydrogen, alkyl ⁇ optionally substituted by halo, hydroxy, C 1-6 alkoxy, C 1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C 1-4 alkyl or C 1-4 alkoxy) ⁇ , phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O) k C 1-4 alkyl, S(O) 2 NH 2 , cyano, C 1-4 alkyl, C 1-4 alkoxy, C(O)NH 2 , C(O)NH(C 1-4 alkyl), CO 2 H, CO 2 (C 1-4 alkyl), NHC(O)(C 1-4 alkyl), NHS(O) 2 (C 1-4 alkyl), C(O)(C 1-4 alkyl), CF 3 or OCF 3 ), heteroaryl (itself optionally substituted by halo, hydroxy, C 1-6 alkoxy, C
  • Table II comprises 409 compounds of formula (Ib): (Ib) Compound LCMS No. X R 2 R 3 (MH+) 1 CO Me pyridin-4-yl 415 2 CO Me fur-3-yl 404 3 CO Me 4-(4-OH-C 6 H 4)C 6 H 4 506 4 CO Me thien-3-yl 419 5 CO Me 2-NO 2 -thien-4-yl 464 6 CO Me pyrazin-2-yl 416 7 CO Me 2,3-Cl 2 -pyridin-5-yl 482 8 CO Me 2-Cl-6-Me-pyridin-4-yl 462 9 CO Me 3-Me-thien-2-yl 434 10 CO Me 3-Me-fur-2-yl 418 11 CO Me 2-CN-pyridin-5-yl 440 12 CO Me 2-NO 2 -thiazol-4-yl 477 13
  • Table IV discloses compounds of formula (Id): (Id) wherein the variables R 14 , X, R 2 and R 3 are as defined in the Table below. Mass Spectrum details are given for certain compounds in Table IV. Compound LCMS No.
  • the compounds of formula (I), (Ia), (Ib), (Ic) or (Id) can be prepared as shown in the processes on pages marked Schemes 1 to 14 below.
  • suitable coupling agents include HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and PyBROP (bromo-tris-pyrrolidinophosphonium hexafluorophosphate) which may be employed according to Example 26.
  • the starting materials for these processes are either commercially available or can be prepared either by literature methods or by adapting literature methods.
  • the invention provides processes for preparing the compounds of formula (I), (Ia), (Ib), (Ic) and (Id). Many of the intermediates in the processes are novel and these are provided as further features of the invention.
  • the compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)). Examples of these conditions are:
  • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); pulmonary fibrosis; asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthmia (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vaso
  • (6) Alzheimer's disease, multiple sclerosis, atherosclerosis, inhibiting the entry of viruses into target cells, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura, disorders of the menstrual cycle, glomerulonephritis or cerebral malaria.
  • AIDS Acquired Immunodeficiency Syndrome
  • Lupus disorders such as lupus erythematosus or systemic lupus
  • erythematosus Hashimoto's thyroiditis
  • myasthenia gravis type I diabetes
  • the compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS).
  • viruses such as human immunodeficiency virus (HIV)
  • HIV human immunodeficiency virus
  • a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis).
  • a method for modulating chemokine receptor activity in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof.
  • the present invention also provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially rheumatoid arthritis).
  • Respiratory disease is, for example, COPD, asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ or rhinitis ⁇ acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis ⁇ ; and is particularly asthma or rhinitis].
  • COPD chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇
  • the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • chemokine receptor activity especially CCR5 receptor activity (especially rheumatoid arthritis)
  • the invention also provides a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis.
  • the present invention provides the use of a compound of the formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man).
  • chemokine receptor activity especially CCR5 receptor activity (especially rheumatoid arthritis)
  • the invention further provides the use of a compound of formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of:
  • obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma ⁇ such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness) ⁇ ; bronchitis ⁇ such as eosinophilic bronchitis ⁇ ; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarco
  • COPD chronic obstruct
  • arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behget's disease, Sjogren's syndrome or systemic sclerosis;
  • Alzheimer's disease Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle;
  • AIDS Acquired Immunodeficiency Syndrome
  • Lupus disorders such as lupus erythematosus or systemic lupus
  • erythematosus Hashimoto's thyroiditis
  • myasthenia gravis myasthenia gravis
  • type I diabetes nephrotic syndrome
  • the present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or solvate thereof.
  • a chemokine mediated disease state especially a CCR5 mediated disease state
  • a warm blooded animal such as man
  • a compound of the invention or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity
  • said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.
  • the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a pharmaceutically acceptable adjuvant diluent or carrier.
  • the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
  • compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration.
  • topical such as to the lung and/or airways or to the skin
  • the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions.
  • a suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient.
  • composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection.
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg ⁇ 1 to 100 mgkg ⁇ 7 of the compound, preferably in the range of 0.1 mgkg ⁇ 1 to 20 mgkg ⁇ 1 of this invention, the composition being administered 1 to 4 times per day.
  • the intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection.
  • the intravenous dose may be given by continuous infusion over a period of time.
  • each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • Buffers such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl ⁇ -cyclodextrin may be used to aid formulation.
  • the above formulations may be obtained by conventional procedures well known in the pharmaceutical art.
  • the tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate.
  • temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C.;
  • chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a “Bond Elut” column is referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, Calif., USA under the name “Mega Bond Elut SI”.
  • IsoluteTM SCX column a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Clamorgan, UK.
  • ArgonautTM PS-tris-amine scavenger resin this means a tris-(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, Calif., USA.
  • (x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer.
  • the LC comprised water symmetry 4.6 ⁇ 50 column C18 with 5 micron particle size.
  • the eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid.
  • the eluent gradient went from 95% A to 95% B in 6 minutes.
  • ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion—(M+H) + and
  • Example 1 The method of Example 1 can be repeated using different acids in place of isonicotinic acid, or different piperidines (such as 4-methylamino-1-(3-R/S-phenylbutyl)piperidine dihydrochloride (Method B), 4-propargylamino-1-(3-R/S-phenylbutyl)piperidine (Method C), 4-allylamino-1-(3,3-diphenylpropyl)piperidine (Method D), 4-allylamino-1-(3-R/S-phenylbutyl)piperidine (Method E) or 4-(cyclopropylmethyl)amino-1-(3-R/S-phenylbutyl)piperidine (Method R)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride.
  • piperidines such as 4-methylamino-1-(3-R/S-phen
  • Example 2 The procedure described in Example 2 can be repeated using different aldehydes in place of 2,6-dimethoxybenzaldehyde or other piperidines (such as 4-methylamino-1-(3,3-diphenylpropyl)piperidine.dihydrochloric acid (Method A) or 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-piperidinyl-N-(2-phenylethyl)-2,4-difluorophenylurea trifluoroacetic acid.
  • piperidines such as 4-methylamino-1-(3,3-diphenylpropyl)piperidine.dihydrochloric acid (Method A) or 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)
  • Example 3 The procedure described in Example 3 can be repeated using different sulphonylchlorides (such as 4-acetamido,3-chlorobenzenesulphonyl chloride) in place of 2-trifluoromethoxybenzenesulphonyl chloride or different piperidines (such as 4amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride.
  • sulphonylchlorides such as 4-acetamido,3-chlorobenzenesulphonyl chloride
  • 2-trifluoromethoxybenzenesulphonyl chloride or different piperidines (such as 4amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-methylamin
  • Example 4 The procedure described in Example 4 can be repeated using various isocyanates or carbamoyl chlorides in place of 3,4-dichlorophenylisocyanate or other piperidines (such as 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G), 4-amino-1-(3-R/S-phenylbutyl)piperidine ditrifluoroacetic acid salt (Method H)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride.
  • piperidines such as 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G), 4-amino-1-(3-R/S-phenylbutyl)piperidine ditrifluoroacetic acid salt (Method H)
  • Example 5 The procedure described in Example 5 can be repeated using different carboxylic acids in place of 2-thiophene carboxylic acid or other piperidines (such as 4-amino-1-(3,3-diphenylpropyl)piperidine (free base from Method G), 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B) or 4-amino-1-(3-R/S-phenylbutyl)piperidine (free base from Method H)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine.
  • piperidines such as 4-amino-1-(3,3-diphenylpropyl)piperidine (free base from Method G), 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B) or 4-amino-1-(3-R/S-phenylbutyl)piperidine (free base from Method H)
  • Example 6 The procedure described in Example 6 can be repeated using different isocyanates or carbamoyl chlorides in place of 3-chlorophenylisocyanate or other piperidines (such as 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine.
  • piperidines such as 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B)
  • N-[1-(3,3-Diphenylpropyl)-4-piperidinyl]-N-methyl-4-fluorosulfonylphenylacetamide (0.005 mmol, in 100 ⁇ L MeCN) and cyclopropylamine (0.01 mmol in 100 ⁇ L MeCN) were mixed and allowed to stand overnight. The solvent was then evaporated to dryness under Genevac high vacuum.
  • N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (323 mg, 1 mmol) was dissolved in DCM (10 mL).
  • Acetic acid (1 ml) and 4,4-diphenyl-2-butanone (384 mg, 1.5 mmol) was added followed by sodium triacetoxyborohydride (516 mg, 2.1 mmol).
  • the reaction mixture was stirred at room temperature for 7 days. Water (10 ml) was added and the layers separated. The organic phase was washed with brine, dried (MgSO 4 ) and evaporated to dryness. The residue was purified by Bond Elut chromatography (eluent 5% MeOH/DCM).
  • N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (480 mg, 1.47 mmol) was dissolved in DCM (40 ml).
  • Acetic acid (6 ml) and 3-(4-chlorophenyl)-3-(4-pyridyl)propionaldehyde (Method BR) (2.2 mmol) was added and the mixture stirred at room temperature for 30 min. followed by the addition of sodium triacetoxyborohydride (340 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 h.
  • Cinnamyl alcohol (5 g, 37 mmol), triethylorthoacetate (47 ml) and propionic acid (0.17 ml) were heated at 140° C. under a distillation head and condenser. After 1 h the reaction mixture was cooled and concentrated to give a pale yellow oil. This oil was dissolved in EtOH (15 ml) and water (15 ml) and NaOH (3.73 g, 93 mmol) was added and the mixture stirred at 80° C. After 16 h the mixture was heated to 100° C. for 2 h then allowed to cool. The reaction mixture was diluted with water (120 ml) and extracted with diethyl ether (2 ⁇ 150 ml).
  • Acetyl chloride (5.5 mL) was added to methanol (20 mL) at 0° C. and the mixture stirred for 10 minutes before addition of a solution of N′-phenylmethyl-N-(1-tert-butyloxycarbonyl-4-piperidinyl)-N-allylurea (1.54 g, 4.17 mmol) in methanol (1 mL). The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 1 h.
  • Step 2 To a solution of ethyl 3-(3-trifluoromethylphenyl)butanoate (Step 2) (1.35 g, 5.2 mmol) in THF (15 ml) at 0° C. was added lithium aluminium hydride (5.2 ml, 1M in THF, 5.2 mmol) and the resulting mixture was stirred for 5 min. Ethyl acetate (10 mL) was added followed by water (0.2 ml) then 6M NaOH solution (0.2 ml) then water (2 ml) and the resulting mixture stirred at room temperature for 5 min. before filtration through Celite®.
  • Step 2 To a solution of ethyl 3-(3-trifluoromethylphenyl)butanoate (Step 2) (1.35 g, 5.2 mmol) in THF (15 ml) at 0° C. was added lithium aluminium hydride (5.2 ml, 1M in THF, 5.2 mmol) and the resulting mixture was
  • Step 1 3-Boc-amino-1-(3,3-diphenylpropyl)pyrrolidine
  • Step 2 3-Amino-1-(3,3-diphenylpropyl)pyrrolidine di-(trifluoroacetic acid) salt
  • Step 1 3-Boc-amino-1-(3,3-diphenylpropyl)pyrrolidine (Step 1) (2.1 g) was dissolved in trifluoroacetic acid (10 mL) and the resulting mixture was stirred at room temperature for 2 h then evaporated giving the title compound (2.3 g).
  • Step 1 3-(4-Chlorophenyl)-3-(4-pyridyl)prop-1-ene
  • Step 1 3-(4-Chlorophenyl)-3-(4-pyridyl)prop-1-ene (Step 1) (0.54 g, 2.2 mmol) was dissolved in MeOH (30 ml) and the solution cooled to ⁇ 78° C. Ozone was bubbled through until a blue colour persisted (20 min.). The mixture was purged with oxygen and dimethyl sulphide (0.33 ml) was added. The mixture was stirred for 1 h while warming to room temperature, then evaporated and the crude product used directly in the next reaction.
  • Step 1 (E)-tert-Butyl 3-(1,3-benzodioxol-5-yl)propenonate
  • Step 2 tert-Butyl 3-(1,3-benzodioxol-5-yl)-3-phenylpropionate

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Abstract

Compounds of formula (I), compositions comprising them, processes for preparing them and their use in medical therapy (for example modulating CCR5 receptor activity in a warm blooded animal).

Description

  • The present invention relates to heterocyclic derivatives having pharmaceutical activity, to processes for preparing such derivatives, to pharmaceutical compositions comprising such derivatives and to the use of such derivatives as active therapeutic agents. [0001]
  • Pharmaceutically active piperidine derivatives are disclosed in EP-A1-1013276, WO00/08013, WO099/38514 and WO099/04794. [0002]
  • Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation and also play a rôle in the maturation of cells of the immune system. Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C, or α) and Cys-Cys (C-C, or β) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity. [0003]
  • The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2). [0004]
  • The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β). [0005]
  • Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above. [0006]
  • The CCR5 receptor is expressed on T-lymphocytes, monocytes, macrophages, dendritic cells, microglia and other cell types. These detect and respond to several chemokines, principally “regulated on activation normal T-cell expressed and secreted” (RANTES), macrophage inflammatory proteins (MIP) MIP-1a and MIP-1b and monocyte chemoattractant protein-2 (MCP-2). [0007]
  • This results in the recruitment of cells of the immune system to sites of disease. In many diseases it is the cells expressing CCR5 which contribute, directly or indirectly, to tissue damage. Consequently, inhibiting the recruitment of these cells is beneficial in a wide range of diseases. [0008]
  • CCR5 is also a co-receptor for HIV-1 and other viruses, allowing these viruses to enter cells. Blocking the receptor with a CCR5 antagonist or inducing receptor internalisation with a CCR5 agonist protects cells from viral infection. [0009]
  • The present invention provides a compound of formula (I): [0010]
    Figure US20040006081A1-20040108-C00001
  • wherein: [0011]
  • R[0012] 1 is C1-6 alkyl, C3-7 cycloalkyl, C3-8 alkenyl or C3-8 alkynyl, each optionally substituted with one or more of: halo, hydroxy, cyano, nitro, C3-7 cycloalkyl, NR8R9, C(O)R10, NR13C(O)R14, C(O)NR17R18, NR19C(O)NR20R21, S(O)nR22, C1-6 alkoxy (itself optionally substituted by heterocyclyl or C(O)NR23R24), heterocyclyl, heterocyclyloxy, aryl, aryloxy, heteroaryl or heteroaryloxy;
  • R[0013] 2 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
  • R[0014] 3 is C1-8 alkyl, C2-8 alkenyl, NR45R46, C2-8 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
  • R[0015] 46 is C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
  • wherein the groups of R[0016] 2, R3 and R46, and the heterocyclyl, aryl and heteroaryl moieties of R1, are independently optionally substituted by one or more of halo, cyano, nitro, hydroxy, S(O)qR25, OC(O)NR26R27, NR28R29, NR30C(O)R31, NR32C(O)NR33R34, S(O)2NR35R36, NR37S(O)2R38, C(O)NR39R40, C(O)R41, CO2R42, NR43CO2R44, C1-6 alkyl, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy;
  • wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O)[0017] kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; the C3-7 cycloalkyl, aryl, heteroaryl and heterocyclyl moieties of R1, R2 and R3 being additionally optionally substituted with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C1-6 alkoxy(C1-6)alkyl;
  • R[0018] 4, R5, R6 and R7 are, independently, hydrogen, C1-6 alkyl {optionally substituted by halo, cyano, hydroxy, C1-4 alkoxy, OCF3, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), N(C1-4 alkyl)C(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), N(C1-4 alkyl)S(O)2(C1-4 alkyl), CO2(C1-4 alkyl), C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, C(O)NH2, CO2H, S(O)2(C1-4 alkyl), S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, heterocyclyl or C(O)(heterocyclyl)}, S(O)2NH2, S(O)2NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, C(O)(C1-4 alkyl), CO2H, CO2(C1-4 alkyl) or C(O)(heterocyclyl); or two of R4, R5, R6 and R7 can join to form, together with the ring to which they are attached, a bicyclic ring system; or two of R4, R5, R6 and R7 can form an endocyclic bond (thereby resulting in an unsaturated ring system);
  • X is C(O), S(O)[0019] 2, C(O)C(O), a direct bond or C(O)C(O)NR47;
  • k, m, n, p and q are, independently, 0, 1 or 2; [0020]
  • R[0021] 25, R26, R27, R28, Re29, R30, R31, R32, R33, R34, R35, R36, R37,
  • R[0022] 38, R39, R40, R41, Re42, R43 and R44 are, independently, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, SCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, N(CH3)2, NHC(O)NH2, C(O)NH2, NHC(O)CH3, S(O)2N(CH3)2, S(O)2NHCH3, CF3, CHF2, CH2F, CH2CF3 or OCF3; and R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R39, R40, R41, R42, R43 and R44 may additionally be hydrogen;
  • R[0023] 8, R9, R10, R13, R14, R17, R18, R19, R20, R21, R23, R24, R45 and R47 are, independently, hydrogen, alkyl {optionally substituted by halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy)}, phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3) or heteroaryl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3);
  • R[0024] 22 is alkyl {optionally substituted by halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy)}, phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy) or heteroaryl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy);
  • the pairs of substituents: R[0025] 8 and R9, R13 and R14, R17 and R18, R20 and R21, R23 and R24, R26 and R27, R28 and R29, R30 and R31, R32 with either R33 or R34, R33 and R34, R35 and R36, R37 and R38, R39 and R40 and R43 and R44 may, independently, join to form a ring and such a ring may also comprise an oxygen, sulphur or nitrogen atom;
  • where for any of the foregoing heterocyclic groups having a ring —N(H)— moiety, that —N(H)— moiety may be optionally substituted by C[0026] 1-4 alkyl (itself optionally substituted by hydroxy), C(O)(C1-4 alkyl), C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2 or S(O)2(C1-4 alkyl);
  • a ring nitrogen and/or sulphur atom is optionally oxidised to form an N-oxide and/or an S-oxide; [0027]
  • foregoing heteroaryl or heterocyclyl rings are C- or, where possible, N-linked; [0028]
  • or a pharmaceutically acceptable salt thereof or a solvate thereof. [0029]
  • Certain compounds of the present invention can exist in different isomeric forms (such as enantiomers, diastereomers, geometric isomers or tautomers). The present invention covers all such isomers and mixtures thereof in all proportions. [0030]
  • Suitable salts include acid addition salts such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate. [0031]
  • The compounds of the invention may exist as solvates (such as hydrates) and the present invention covers all such solvates. [0032]
  • Alkyl groups and moieties are straight or branched chain and are, for example, methyl, ethyl, n-propyl or iso-propyl. [0033]
  • Alkenyl and alkynyl groups and moieties are, for example, vinyl, allyl or propargyl. [0034]
  • Cycloalkyl is a mono-, bi- or tri-cyclic structure such as, for example, cyclopropyl, cyclopentyl, cyclohexyl or adamantyl. [0035]
  • Cycloalkenyl comprises one double bond and is, for example, cyclopentenyl or cyclohexenyl. [0036]
  • Acyl is, for example, carbonyl substituted by either C[0037] 1-6 alkyl or optionally substituted phenyl.
  • Heterocyclyl is a non-aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heterocyclyl is, for example, piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or tetrahydrofuryl. [0038]
  • Heteroaryl is an aromatic 5 or 6 membered ring comprising at least one heteroatom selected from the group comprising nitrogen, oxygen and sulphur. Heteroaryl is, for example, pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, indolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl, phthalazinyl, indanyl, oxadiazolyl or benzthiazolyl. [0039]
  • Aryl is a carbocyclic aromatic ring system (for example phenyl or naphthyl). [0040]
  • Arylalkyl is, for example, benzyl, 1-(phenyl)ethyl or 2-(phenyl)ethyl. [0041]
  • Heteroarylalkyl is, for example, pyridinylmethyl, pyrimidinylmethyl or 2-(pyridinyl)ethyl. [0042]
  • When R[0043] 39 and R40 join to form a ring the ring is, for example, a piperazinyl, piperidinyl, pyrrolidinyl or morpholinyl ring.
  • In one aspect the invention provides a compound of formula (I) wherein X is C(O), S(O)[0044] 2 or a direct bond. In a further aspect X is C(O).
  • In another aspect the invention provides a compound of formula (I) wherein m and p are both 1. [0045]
  • In a further aspect the invention provides a compound of formula (I) wherein R[0046] 4, R5, R6 and R7 are all hydrogen.
  • In yet another aspect the invention provides a compound of formula (I) wherein R[0047] 2 is hydrogen, C1-4 alkyl (optionally substituted by C3-6 cycloalkyl or phenyl), C3-4 alkenyl or C3-4 alkynyl. In another aspect R2 is hydrogen.
  • In another aspect the invention provides a compound of formula (I) wherein R[0048] 2 is methyl, ethyl, allyl, cyclopropyl or propargyl.
  • In a further aspect the invention provides a compound of formula (I) wherein R[0049] 2 is methyl, ethyl or allyl.
  • In a still further aspect the invention provides a compound of formula (I) wherein R[0050] 2 is C3-8 alkenyl (such as allyl) or C3-7 cycloalkyl (such as cyclopropyl).
  • In a further aspect X is C(O). [0051]
  • In a still further aspect R[0052] 3 is NR45R46, aryl, heteroaryl, aryl(C1-4)alkyl or heteroaryl(C1-4)alkyl; R45 is hydrogen or C1-6 alkyl; R46 is aryl, heteroaryl, aryl(C1-4)alkyl or heteroaryl(C1-4)alkyl; wherein the aryl and heteroaryl groups of R3 and R46 are independently substituted by S(O)qR25, OC(O)NR26R27, NR32C(O)NR33R34 or C(O)R41, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy(C1-6)alkyl, S(O)qR25, OC(O)NR26R27, NR28R29, NR30C(O)R31, NR32C(O)NR33R34, S(O)2NR35R36, NR37S(O)2R38, C(O)NR39R40, C(O)R41, CO2R42, NR43CO2R44, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy;
  • wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O)[0053] kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; wherein q, ke, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 and R44 are as defined above.
  • In a still further aspect R[0054] 3 is NR45R46, phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; R45 is hydrogen or C1-6 alkyl; R46 is phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; wherein the phenyl and heteroaryl groups of R3 and R46 are substituted by S(O)2R25, OC(O)NR26R27, NR32C(O)NR33R34 or C(O)R41, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy(C1-6)alkyl, S(O)2R25, OC(O)NR26R27, NR28R29, NR30C(O)R31, NR32C(O)NR33R34, S(O)2NR35R36, NR37S(O)2R38, C(O)NR39R40, C(O)R41, CO2R42, NR CO2R43CO2R44, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy; wherein R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 and R44 are as defined above.
  • In another aspect R[0055] 3 is NR45R46, phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; R45 is hydrogen or C1-6 alkyl; R46 is phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; wherein the phenyl and heteroaryl groups of R3 and R46 are substituted by S(O)2R25, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy(C1-6)alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy; wherein R25 is C1-6 alkyl.
  • In yet another aspect R[0056] 3 is NR45R46, phenyl or phenylCH2; R45 is hydrogen or C1-2 alkyl; R46 is phenyl or phenylCH2; wherein the phenyl groups of R3 and R46 are mono-substituted by S(O)2R25; wherein R25 is C1-6 alkyl (for example methyl).
  • In a further aspect R[0057] 3 is phenyl or phenylCH2; wherein the phenyl groups are mono-substituted (for example in the 4-position) by S(O)2R25; wherein R25 is C1-6 alkyl (for example methyl).
  • In another aspect R[0058] 3 is NR45R46, phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; R45 is hydrogen or C1-6 alkyl; R46 is phenyl, heteroaryl, phenyl(C1-4)alkyl or heteroaryl(C1-4)alkyl; wherein the phenyl and heteroaryl groups of R3 and R46 are substituted by S(O)2NR35R36, and optionally further substituted byone or more of halo, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy(C1-6)alkyl, C1-6 haloalkyl, C1-6 alkoxy or C1-6 haloalkoxy; wherein R35 and R36 are, independently, hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, SCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, N(CH3)2, NHC(O)NH2, C(O)NH2, NHC(O)CH3, S(O)2N(CH3)2, S(O)2NHCH3, CF3, CHF2, CH2F, CH2CF3 or OCF3.
  • In yet another aspect R[0059] 3 is NR45R46, phenyl or phenylCH2; R45 is hydrogen or C1-2 alkyl; R46 is phenyl or phenylCH2; wherein the phenyl groups of R3 and R46 are mono-substituted by S(O)2NR35R36; wherein R35 and R36 are, independently, hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C1-4 alkoxy, SCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, N(CH3)2, NHC(O)NH2, C(O)NH2, NHC(O)CH3, S(O)2N(CH3)2, S(O)2NHCH3, CF3, CHF2, CH2F, CH2CF3 or OCF3; where, in a further aspect, R35 is neither hydrogen nor C1-4 alkyl.
  • In another aspect the present invention provides a compound of formula (I) wherein X is C(O); and R[0060] 3 is C3-7 cycloalkyl, (CH2)3-aryl, (CH2)3-heteroaryl, (CH2)aryl, (CH2)-heteroaryl, (CH2)3C(═O)NH-aryl, (CH2)3C(═O)NH-heteroaryl, (CH2)C3-10 cycloalkyl, (CH2)5NO2, (CH2)5NC(═O)C1-4 alkyl, CH2—CH═CH-aryl, CH2—CH═CH-heteroaryl, NH-aryl, NH-heterocyclyl, NH-allyl, NHCH2-aryl or NHCH2-heteroaryl; wherein aryl, heteroaryl and heterocyclyl groups are optionally substituted as defined above.
  • In a further aspect the present invention provides a compound of formula (I) wherein X is C(O); and R[0061] 3 is (CH2)3-aryl, (CH2)3-heteroaryl, (CH2)aryl, (CH2)-heteroaryl, (CH2)3C(═O)NH-aryl, (CH2)3C(═O)NH-heteroaryl, NH-aryl, NH-heterocyclyl, NHCH2-aryl or NHCH2-heteroaryl; wherein aryl, heteroaryl and heterocyclyl rings are optionally substituted as defined above.
  • In a still further aspect the present invention provides a compound of formula (I) wherein X is C(O); and R[0062] 3 is CH2-phenyl (wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more substituents recited for aryl above), (CH2)3-phenyl, (CH2)3-oxadiazole-aryl, (CH2)3-oxadiazole-heteroaryl, (CH2)3C(═O)NH-phenyl, NHCH2-phenyl, NHCH2-heteroaryl or NH-phenyl (wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more substituents recited for aryl above); wherein aryl and heteroaryl rings are optionally substituted as defined above; phenyl rings are, unless stated otherwise, optionally substituted with one or more substituents recited for aryl above.
  • In yet another aspect the present invention provides a compound of formula (I) wherein X is C(O); and R[0063] 3 is CH2-phenyl [wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more of Cl, Br, F, OH, C1-4 alkoxy (such as OMe or OEt), CN, S(O)2(C1-4 alkyl) (such as S(O)2Me), S(O)(C1-4 alkyl) (such as S(O)Me), S(C1-4 alkyl) (such as SMe), S(O)2NH2, S(O)2N(C1-4 alkyl)2 (such as S(O)2NMe2), C1-4 alkyl (such as Me), CF3, OCF3, NO2, NHC(O)(C1-4 alkyl) (such as NHCOMe), C(O)(C1-4 alkyl) (such as C(O)Me), S(O)2CF3, S(O)CF3, SCF3, C(O)NH2 or CO2(C1-4 alkyl) (such as CO2Me)], NHCH2-phenyl [wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more of Cl, Br, F, OH, C1-4 alkoxy (such as OMe or OEt), CN, S(O)2(C1-4 alkyl) (such as S(O)2Me), S(O)(C1-4 alkyl) (such as S(O)Me), S(C1-4 alkyl) (such as SMe), S(O)2NH2, S(O)2N(C1-4 alkyl)2 (such as S(O)2NMe2), CF3, OCF3, NO2, NHC(O)(C1-4 alkyl such as NHC(O)Me), C(O)(C1-4 alkyl) (such as C(O)Me), S(O)2CF3, S(O)CF3, SCF3, C(O)NH2 or CO2(C1-4 alkyl) (such as CO2Me)] or NH-phenyl [wherein the phenyl ring is optionally substituted at the 3-, 4- and/or 5-position with one or more of F, Cl, C1-4 alkoxy (such as OMe) or N(C1-4 alkyl)2 (such as NMe2)].
  • In another aspect the present invention provides a compound of formula (I) wherein X is C(O); and R[0064] 3 is CH2-phenyl [wherein the phenyl ring is optionally substituted at the 4-position with Cl, Br, F, OH, OMe, CN, S(O)2Me, S(O)2NH2, S(O)2NMe2, CF3, OCF3, NO2, NHC(O)Me or CO2Me], NHCH2-phenyl [wherein the phenyl ring is optionally substituted at the 4-position with Cl, Me, F or OMe] or NH-phenyl [wherein the phenyl ring is optionally substituted at the 4-position with F, Cl, OMe or NMe2).
  • In a further aspect the invention provides a compound as hereinbefore defined wherein R[0065] 1 is C1-6 alkyl {optionally substituted by cyano, NR13*C(O)R14*, NR15*R16*, phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3) or heteroaryl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3, OCF3 or phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3))} or C2-6 alkenyl {optionally substituted by phenyl (itself optionally substituted by halogen, hydroxy, nitro, C1-4 alkyl, C1-4 alkoxy or di(C1-4 alkyl)amino)}; R13* is C1-4 alkyl; R14* is phenyl optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; and R15* and R16* are, independently, C1-4 alkyl or phenyl (optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3). Heteroaryl is, for example, pyrrolyl, furyl, indolyl or pyrimidinyl.
  • In another aspect R[0066] 1 is a three-carbon chain which optionally carries one methyl group along its length (for example a methyl group is carried on the carbon that bonds to the nitrogen atom of the ring shown in formula (I)) wherein said three-carbon chain is optionally substituted as described for R1 above.
  • In a still further aspect the invention provides a compound as hereinbefore defined wherein R[0067] 1 is 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4-dimethoxy-6-hydroxybenzyl, 3-(4-dimethylamino-phenyl)prop-2-enyl, (1-phenyl-2,5-dimethylpyrrol-3-yl)methyl, 2-phenylethyl, 3-phenylpropyl, 3-R/S-phenylbutyl, 3-cyano-3,3-diphenylpropyl, 3-cyano-3-phenylpropyl, 4-(N-methylbenzamido)-3-phenylbutyl or 3,3-diphenylpropyl.
  • Further examples of R[0068] 1 include each individual partial structure presented in Schedule I and each individual partial structure presented in Schedule I can be combined with any definition of X, R2, R3, R4, R5, R6, R7, m or p as herein defined.
  • In another aspect the invention provides a compound as hereinbefore defined wherein R[0069] 1 is 3-R/S-phenylbutyl or, preferably, 3,3-diphenylpropyl. In a further aspect R1 is 3-(S)-phenylbutyl. In yet a further aspect R1 is 3,3-diphenylpropyl.
  • In a still further aspect the present invention provides a compound of formula (I) wherein R[0070] 1 is a hereinbefore defined; R2 is ethyl, allyl or cyclopropyl (for example allyl or cyclopropyl); and R3 is NHCH2C6H5, NHCH2(4-F—C6H4), NHCH2(4-S(O)2CH3—C6H4), NHCH2(4-S(O)2NH2—C6H4), CH2C6H5, CH2(4-F—C6H4), CH2(4-S(O)2CH3—C6H4) or CH2(4-S(O)2NH2—C6H4) {for example NHCH2(4-S(O)2CH3—C6H4) or CH2(4-S(O)2CH3—C6H4)}.
  • In yet another aspect the present invention provides a compound of formula (I) wherein R[0071] 1 is 3,3-diphenylpropyl, X is CO, R2 is C1-8 alkyl, and R3 is as hereinbefore defined.
  • In a further aspect the present invention provides a compound of formula (I) wherein R[0072] 1 is 3,3-diphenylpropyl, X is CO, R2 is allyl, and R3 is as hereinbefore defined.
  • In a still further aspect the present invention provides a compound of formula (I) wherein R[0073] 1 is 3,3-diphenylpropyl or 3-R/S-phenylbutyl, X is C(O), R2 is H, and R3 is as hereinbefore defined.
  • In another aspect the present invention provides a compound of formula (I) wherein R[0074] 1 is 3,3-diphenylpropyl or 3-R/S-phenylbutyl, X is C(O), R2 is H or methyl, and R3 is NR45R46 (such as an amine group as hereinbefore defined for R3).
  • In yet another aspect the present invention provides a compound of formula (Ia): [0075]
    Figure US20040006081A1-20040108-C00002
  • wherein X, R[0076] 2 and R3 are as defined above.
  • In a further aspect the present invention provides a compound of formula (Ib): [0077]
    Figure US20040006081A1-20040108-C00003
  • wherein X, R[0078] 2 and R3 are as defined above.
  • In a still further aspect the present invention provides a compound of formula (Ic): [0079]
    Figure US20040006081A1-20040108-C00004
  • wherein X, m, R[0080] 1, R2 and R3 are as defined above.
  • In yet another aspect the present invention provides a compound of formula (Id): [0081]
    Figure US20040006081A1-20040108-C00005
  • wherein X, R[0082] 2 and R3 are as defined above; and R14 is hydrogen, alkyl {optionally substituted by halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy)}, phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3), heteroaryl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4alkyl), C(O)(C1-4 alkyl), CF3 or OCF3) or NR20OR21; wherein R20 and R21, together with the nitrogen to which they are attached, join to form an aziridine, azetidine or pyrrolidine ring.
  • The following compounds illustrate the invention. [0083]
    TABLE I
    Table I lists compounds of formula (Ia):
    Figure US20040006081A1-20040108-C00006
         		(Ia)
  • wherein X, R[0084] 2 and R3 are listed in the table. Mass Spectrum details are given for certain compounds of Table I.
    TABLE II
    Table II comprises 409 compounds of formula (Ib):
    (Ib)
    Figure US20040006081A1-20040108-C00007
    Compound LCMS
    No. X R2 R3 (MH+)
    1 CO Me pyridin-4-yl 415
    2 CO Me fur-3-yl 404
    3 CO Me 4-(4-OH-C6H4)C 6H4 506
    4 CO Me thien-3-yl 419
    5 CO Me 2-NO2-thien-4-yl 464
    6 CO Me pyrazin-2-yl 416
    7 CO Me 2,3-Cl2-pyridin-5-yl 482
    8 CO Me 2-Cl-6-Me-pyridin-4-yl 462
    9 CO Me 3-Me-thien-2-yl 434
    10 CO Me 3-Me-fur-2-yl 418
    11 CO Me 2-CN-pyridin-5-yl 440
    12 CO Me 2-NO2-thiazol-4-yl 477
    13 CO Me (CH2)5C6H5 483
    14 CO Me (CH2)2CONH(4-MeO-C6H4) 514
    15 CO Me cyclopent-1-en-1-yl 403
    16 CO Me (CH2)7COC6H5 540
    17 CO Me 4-tert-butyl-cyclohexyl 476
    18 CO Me 2-Me-4,5,6,7-F4-benzofur-3-yl 539
    19 CO Me (CH2)3(3,4-(MeO)2—C6H3) 516
    20 CO Me (CH2)3CONH(C6H5) 499
    21 CO Me (CH2)2S(benzothiazol-2-yl) 530
    22 CO Me (CH2)3CONH(2-CN—C6H4) 524
    23 CO Me CH2(1-phenyl-5-methyl-iniidazol-4-yl) 508
    24 CO Me CH2(adamant-1-yl) 486
    25 CO Me (CH2)3(1-Me-1,2-dihydro- 537
    isoquinolin-1-on-3-yl)
    26 CO Me CH2(4-hydroxy-phthalazin-1-yl) 496
    27 CO Me CH2(1-Me-cyclohexyl) 448
    28 Co Me CH2(indan-2-yl) 468
    29 Co Me 3-F-4-NO2—C6H3 476
    30 Co Me CH2NH(C6H5) 443
    31 CO Me (CH2)5NO2 453
    32 Co Me 2-Cl-pyridin-4-yl 448
    33 CO Me (CH2)5NHCOCF3 517
    34 CO Me CH2(2-Me-3-NO2—C6H3) 486
    35 CO Me CH2(3,5-(MeO)2—C6H3) 488
    36 CO CH2CH═CH2 CH2(4-EtO—C6H4) 497
    37 CO CH2CH═CH2 CH2(5-F-indol-3-yl) 510
    38 CO CH2CH═CH2 CH2(3,4-(MeO)2—C6H3) 513
    39 CO CH2CH═CH2 CH2(3,4,5-(MeO)3—C6H2) 543
    40 CO CH2CH═CH2 (CH2)3COC6H5 509
    41 CO CH2CH═CH2 CH2(indol-3-yl) 492
    42 CO CH2CH═CH2 CH2(3,4-methylenedioxy-C6H3) 497
    43 CO CH2CH═CH2 CH2(4-I—C6H4) 579
    44 CO CH2CH═CH2 CH2(4-OCF3—C6H4) 537
    45 CO CH2CH═CH2 CH2(3-Me-4-MeO—C6H3) 497
    46 CO CH2CH═CH2 CH2(3,4-(MeO)2—C6H3) 527
    47 CO CH2CH═CH2 CH2(3-CF3-4-F—C6H3) 539
    48 CO CH2CH═CH2 CH2(benzthien-3-yl) 509
    49 CO CH2CH═CH2 (CH2)3(3-(pyridin-2-yl)-1,2,4- 550
    oxadiazol-5-yl)
    50 CO CH2CH═CH2 (CH2)3CO(thien-2-yl) 515
    51 CO CH2CH═CH2 (CH2)3(4-Me—C6H4) 495
    52 CO CH2CH═CH2 CH2(5-MeO-indol-3-yl) 522
    53 S(O)2 Me 2-OCF3—C6H4 533
    54 S(O)2 Me 3-NO2-4-Cl-C6H3 528
    55 S(O)2 Me 2,5-Cl2—C6H3 517
    56 S(O)2 Me 2,5-Cl2-thien-3-yl 523
    57 S(O)2 Me 2-Cl-5-CF3—C6H3 551
    58 S(O)2 Me 2-Cl-thien-2-yl 489
    59 S(O)2 Me 2-Cl-4-CF3—C6H3 551
    60 S(O)2 Me 2,4-F2—C6H3 485
    61 S(O)2 Me 2,3-Cl2—C6H3 517
    62 S(O)2 Me 2-NO2—C6H4 494
    63 S(O)2 Me 3-Cl-4-(NHCOMe)—C6H3 540
    64 S(O)2 Me 2-CF3—C6H4 517
    65 S(O)2 Me 3,5-Me2-isoxazol-4-yl 468
    66 S(O)2 Me 2-(isoxazol-3-yl)thien-5-yl 522
    67 S(O)2 H 3-Cl-4-(NHCOMe)—C6H3 526
    68 CO Me NH(3,4-Cl2—C6H3) 496
    69 CO Me NH(3-Cl-4-Me-C6H3) 476
    70 CO Me NH(4-CF3—C6H4) 496
    71 CO Me NH(4-COMe—C6H4) 471
    72 CO Me NH(2-Me-5-NO2—C6H3) 487
    73 CO Me NH(3,4-F2—C6H3) 464
    74 CO Me NH(CH2)2thien-2-yl 462
    75 CO Me NH(4-I—C6H4) 554
    76 CO Me NH(2-Et—C6H4) 457
    77 CO Me NH(2,6-(Me)2—C6H3) 457
    78 CO Me NHCH2(2,4-Cl2—C6H3) 510
    79 CO H NHCH2C6H5 428
    80 CO H NH(4-Br—C6H4) 494
    81 CO H NH(4-Cl—C6H4) 448
    82 CO H NH(2-Cl—C6H4) 448
    83 CO H NH(4-Me—C6H4) 428
    84 CO H NH(2,6-Me2-4-Br—C6H2) 522
    85 CO H NH(2,4,6-Me3—C6H2) 456
    86 CO H NH(2-NO2-4-Me—C6H3) 473
    87 CO H NH(3-NO2-4-Me—C6H3) 473
    88 CO H NH(2-Me-3-NO2—C6H3) 473
    89 CO H NH(4-MeO—C6H4) 444
    90 CO H NH(CH2)2thien-2-yl 448
    91 CO H NH-(n-propyl) 380
    92 CO H NH(2,6-Me2—C6H3) 442
    93 CO H NH(2,6-F2—C6H3) 450
    94 CO H NH(4-NMe2—C6H4) 457
    95 CO H NHCH2(2-Me—C6H4) 442
    96 CO Me thien-2-yl 419
    97 CO Me 2-NO2-thien-5-yl 448
    98 CO Me 3-NO2—C6H4 458
    99 CO Me 4-NO2—C6H4 458
    100 CO Me 4-F—C6H4 431
    101 CO Me 2-Cl-pyridin-5-yl 448
    102 CO Me fur-2-yl 403
    103 CO Me CH2(4-Br—C6H4) 507
    104 CO Me (CH2)2CO2Me 423
    105 CO Me cyclobutyl 391
    106 CO Me (CH2)3(2-MeO—C6H4) 471
    107 CO Me 1-(4-MeO—C6H4)cyclopropyl 483
    108 CO Me (CH2)3indol-3-yl 494
    109 COCO Me CH2CH(CH3)2 421
    110 CO Me benzyl 427
    111 CO Me CH2(3,4-Cl2—C6H3) 495
    112 CO Me CH2(tert-butyl) 407
    113 CO Me CH2(3,4,5-(MeO)3—C6H2) 517
    114 CO Me CH2CH(CH3)2 393
    115 CO Me CH2CH═CHC6H5 453
    116 CO Me CH2CH2SCH3 411
    117 CO Me CH2(4-Cl—C6H4) 461
    118 CO Me 2,6-Cl2-pyridin-3-yl 482
    119 CO Me CH2(2-F—C6H4) 445
    120 CO Me CH2(3-F—C6H4) 445
    121 COCO Me phenyl 441
    122 CO Me CH2(2-Cl—C6H4) 461
    123 CO Me CH2(3-Cl—C6H4) 461
    124 CO Me CH2(3-MeO—C6H4) 457
    125 CO Me CH2(3,4-(MeO)2—C6H3) 487
    126 CO Me CH2(4-F—C6H4) 445
    127 CO Me CH2(4-MeO—C6H4) 457
    128 CO Me CH2(2,4-F2—C6H3) 463
    129 CO Me CH2(thien-2-yl) 433
    130 CO Me CH2(thien-3-yl) 433
    131 CO Me CH2(indol-3-yl) 466
    132 CO Me CH2(2,4-Cl2—C6H3) 495
    133 CO Me CH2(3,4-F2—C6H3) 463
    134 CO Me CH2(4-CF3—C6H4) 495
    135 CO Me CH2(4-CF3O-C6H4) 511
    136 CO Me CHMe(C6H5) 441
    137 CO Me CH2(benzthien-3-yl) 483
    138 CO Me CH2(4-NO2—C6H4) 472
    139 CO Me (CH2)3(3-(pyridin-2-yl)-1,2,4- 524
    oxadiazol-5-yl)
    140 CO H CH2(4-NO2—C6H4) 458
    141 CO H CH2(3,4,5-(MeO)3—C6H2) 503
    142 CO H (CH2)3(3-(pyridin-2-yl)-1,2,4- 510
    oxadiazol-5-yl)
    143 CO H CH2(4-Cl—C6H4) 447
    144 CO Me NH(3-Cl—C6H4) 462
    145 CO Me NHCH2C6H5 442
    146 CO Me NH(cyclohexyl) 434
    147 CO Me NH(phenyl) 428
    148 CO Me NH(2-MeO—C6H4) 458
    149 CO Me NH(3-Me—C6H4) 442
    150 CO Me NH(4-Br—C6H4) 508
    151 CO Me NH(4-Cl—C6H4) 462
    152 CO Me NH(4-NO2—C6H4) 473
    153 CO Me NH(2-Br—C6H4) 508
    154 CO Me NH(4-CO2Et—C6H4) 500
    155 CO Me NH(2-F—C6H4) 446
    156 CO Me NH(2-Cl—C6H4) 462
    157 CO Me NH(4-Me—C6H4) 442
    158 CO Me NH(2,4,6-Me3—C6H2) 470
    159 CO Me NH(2-NO2-4-Me—C6H3) 487
    160 CO Me NH(2-Me-4-Cl—C6H3) 476
    161 CO Me NH(3-CN—C6H4) 453
    162 CO Me NH(3-NO2-4-Me—C6H3) 487
    163 CO Me NH(3-COMe—C6H4) 470
    164 CO Me NH(3,5-Me2—C6H3) 456
    165 CO Me NH(2,4-Me2—C6H3) 456
    166 CO Me NH(2-Cl-4-NO2—C6H3) 507
    167 CO Me NH(2-Me-3-NO2—C6H3) 487
    168 CO Me NH(4-MeO—C6H4) 458
    169 CO Me NH(n-propyl) 394
    170 CO Me NHEt 380
    171 CO Me NH(2-phenyl-cyclopropyl) 468
    172 CO Me NH(CH2CH═CH2) 392
    173 CO Me NH(naphth-2-yl) 478
    174 CO Me NH(CH2)2C6H5 456
    175 CO Me NH(2,6-Cl2-pyridin-4-yl) 497
    176 CO Me NH(2,6-F2—C6H3) 464
    177 CO Me NH(4-N(Me)2—C6H4) 471
    178 CO Me NH(naphth-1-yl) 478
    179 CO Me NH(2-Me—C6H4) 442
    180 CO Me NH(2,6-Cl2—C6H3) 496
    181 CO Me NH(CH2)5CO2Et 494
    182 bond Me CH2(4-Cl-imidazol-3-yl) 424
    183 bond Me CH2(2-(4-NO2—C6H4)fur-5-yl) 511
    184 bond Me CH2(3-OH-4-NO2—C6H3) 461
    185 bond Me CH2(4-Br-imidazol-3-yl) 469
    186 bond Me CH2(1-(4-Cl-benzyl)-imidazol-3-yl) 514
    187 bond H CH2(3-NO2-4-OH—C6H3) 447
    188 bond H CH2(3-OH-4-NO2—C6H3) 447
    189 CO Me CH2(2,2-Me2-3-(COMe)-cyclobutyl)
    190 CO Me CH2(3-MeO-4-OH-C6H3)
    191 CO Me CH2(5-OH-indol-3-yl)
    192 CO Me CH2(5-F-indol-3-yl)
    193 CO Me CH2(4-OH—C6H4) 443
    194 CO CH2C≡CH (CH2)3cyclohexyl
    195 CO CH2C≡CH CH2CH2CH(CH3)C6H5
    196 CO CH2CH═CH2 (CH2)3cyclohexyl
    197 CO CH2CH═CH2 CH2(benzthien-3-yl)
    198 CO CH2CH═CH2 CH2(4-(S(O)2Me)—C6H4) 536
    199 CO CH2cyclopropyl (CH2)3cyclohexyl
    200 CO (CH2)2phenyl NH(2,4-F2—C6H3)
    201 CO H NH(3,4-Cl2—C6H3)
    202 CO H NH(2,4-Me2—C6H3)
    203 CO H NH(2-Cl-4-NO2—C6H3)
    204 CO H NH(4-MeO—C6H4)
    205 CO H NHCH2(2,4-Cl2—C6H3)
    206 CO Me CH2(4-Me—C6H4) 441
    207 CO H CH2(3-Me—C6H4)
    208 CO H benzyl
    209 CO H CH2(4-EtO—C6H4)
    210 CO H CH2(3-F—C6H4)
    211 CO H CH2(4-iso-propyl-C6H4)
    212 CO H CH2-3-indole-5-OH
    213 CO H CH2(4-Me—C6H4)
    214 CO H CH2(3-Me-4-MeO—C6H3)
    215 CO H 5-F-indol-3-yl
    216 CO H CH2(3,4-Cl2—C6H3)
    217 CO H CH2(4-phenyl-C6H4)
    218 CO H CH2(3,4-F2—C6H3)
    219 CO H CH2(4-CF3O—C6H4) 497
    220 CO H CH2(3-Br-4-MeO—C6H3)
    221 CO H CH2(3-CF3-4-F—C6H3)
    222 CO H CH2(benzthien-3-yl)
    223 CO H CH2(4-(S(O)2NH2)—C6H4)
    224 CO H CH2(4-(S(O)2NMe2)—C6H4)
    225 CO H CH2(3-CF3—C6H4)
    226 CO H CH2(3-Br—C6H4)
    227 CO H CH2(4-Br—C6H4)
    228 CO H CH2(4-(4-F—C6H4)—C6H4)
    229 CO Me NH(4-CF3O—C6H4)
    230 CO Me NH(3-F—C6H4)
    231 CO Me NH(2,4-F2—C6H3)
    232 CO H CH2(4-NH2—C6H4)
    233 CO CH2CH═CH2 CH2(3,5-(MeO)2-4-OH—C6H2) 529
    234 CO Me CH2(4-CN—C6H4) 452
    235 CO Me CH2(4-(S(O)2NH2)—C6H4) 506
    236 CO Me CH2(4-(S(O)2NMe2)—C6H4) 534
    237 CO H CH2(3,4-(OMe)2—C6H3) 473
    238 CO H CH2(4-OMe—C6H4) 443
    239 CO H CH2(4-OH—C6H4) 429
    240 CO H CH2(4-CF3—C6H4) 481
    241 CO H CH2(4-F—C6H4) 431
    242 CO H CH2(3-CF3—C6H4)
    243 CO CH2CH═CH2 NH(4-F—C6H4) 472
    244 CO CH2CH═CH2 NH(4-CH3—C6H4) 468
    245 CO CH2CH═CH2 NHCH2C6H5 468
    246 CO CH2CH═CH2 NH(phenyl) 454
    247 CO CH2CH═CH2 NH(4-OCH3—C6H4) 484
    248 CO CH2CH═CH2 NH((S)—CH3CH(phenyl)) 482
    249 CO CH2CH═CH2 NHCH2CH═CH2 418
    250 CO CH2CH═CH2 NHCH2(3-CH3—C6H4) 482
    251 CO CH2CH═CH2 NHCH2(4-OCH3—C6H4) 498
    252 CO CH2CH═CH2 NHCH2(4-CH3—C6H4) 482
    253 CO CH2CH═CH2 NHCH2(4-F—C6H4) 486
    254 CO Et CH2(4-F—C6H4) 459
    255 CO Et CH2(4-Cl—C6H4) 475
    256 CO Et CH2(4-NO2—C6H4) 486
    257 CO Et CH2(4-CN—C6H4) 466
    258 CO Et CH2(4-S(O)2NH2—C6H4) 520
    259 CO Et CH2(4-S(O)2N(CH3)2—C6H4) 548
    260 CO Et NH(4-Me—C6H4) 456
    261 CO Et NH(CHCH3C6H5) 470
    262 CO Et NHCH2CH═CH2 406
    263 CO Et NHCH2C6H5 456
    264 CO Et NHCH2(3-Me—C6H4) 470
    265 CO Et NHCH2(4-OMe—C6H4) 486
    266 CO Et NHCH2(4-Me—C6H4) 470
    267 CO Et NHCH2(4-F—C6H4) 474
    268 CO Me CH2(4-(OCH2C6H4)—C6H4) 533
    269 CO CH2CH═CH2 CH2(3-F—C6H4) 471
    270 CO CH2CH═CH2 (CH2)3-3-(4-Cl—C6H4)— 583
    [1,2,4]oxadiazol-5-yl (585)
    271 CO CH2CH═CH2 (CH2)3-3-(3-NO2—C6H4)— 594
    [1,2,4]oxadiazol-5-yl
    272 CO CH2CH═CH2 CH2(3-OMe—C6H4) 483
    273 CO CH2CH═CH2 CH2(4-Br—C6H4) 533/531
    274 CO CH2CH═CH2 CH2(4-Cl—C6H4) 487
    (489)
    275 CO CH2CH═CH2 CH2(4-OMe—C6H4) 483
    276 CO CH2CH═CH2 CH2(4-CF3—C6H4) 521
    277 CO Me CH2(4-NHC(O)Me—C6H4) 484
    278 CO Me CH2(4-SMe—C6H4) 473
    279 CO Me CH2(4-CO2Me—C6H4) 485
    280 CO CH2CH═CH2 CH2(3,5-(OMe)2-4-OH—C6H4 529
    281 CO Me CH2(4-S(O)2Me—C6H4) 505
    282 CO Et CH2(4-OCF3—C6H4) 525
    283 CO Et CH2(4-S(O)2Me—C6H4) 519
    284 CO cPr CH2(4-NO2—C6H4) 498
    285 CO cPr CH2(4-OCF3—C6H4) 537
    286 CO cPr CH2(4-S(O)2Me—C6H4) 531
    287 CO cPr CH2(4-S(O)2NH2—C6H4) 532
    288 CO cPr CH2(4-F—C6H4) 471
    289 CO (CH2)2OH CH2(4-NO2—C6H4) 502
    290 CO (CH2)2OH CH2(4-OCF3C6H4) 541
    291 CO (CH2)2OH CH2(4-S(O)2Me—C6H4) 535
    292 CO (CH2)2OH CH2(4-S(O)2NH2—C6H4) 536
    293 CO (CH2)2OH CH2(4-F—C6H4) 475
    294 CO (CH2)2F CH2(4-NO2—C6H4) 504
    295 CO (CH2)2F CH2(4-OCF3—C6H4) 543
    296 CO (CH2)2F CH2(4-S(O)2Me—C6H4) 537
    297 CO (CH2)2F CH2(4-S(O)2NH2—C6H4) 538
    298 CO (CH2)2F CH2(4-F—C6H4) 477
    299 CO CH2CH═CH2 CH2(4-NO2—C6H4) 498
    300 CO CH2CH═CH2 CH2(4-S(O)2NH2—C6H4) 532
    301 CO CH2CH═CH2 CH2(4-F—C6H4) 471
    302 CO cPr CH2(pyridin-2-yl) 454
    303 CO cPr CH2(1-Me-imidazol-4-yl) 457
    304 CO cPr CH2(1-Me-4-NO2-pyrazo1-5-yl) 502
    305 CO cPr CH2(6-Cl-pyridin-3-yl) 488
    (490)
    306 CO cPr CH2(3-Me-isoxazol-5-yl) 458
    307 CO cPr CH2(3,5-Me2-isoxazol-4-yl) 472
    308 CO Et CH2(5-Cl-thien-2-yl) 481
    (483)
    309 CO Et CH2(5-(NHCO2-tert-Bu)- 564
    [2,4]oxadiazol-3-yl)
    310 CO Et CH2(6-Cl-pyridin-3-yl) 476
    (478)
    311 CO Et CH2(3,5-Me2-isoxazol-4-yl) 460
    312 CO Et CH2(3-Me-isoxazol-5-yl) 446
    313 CO Et CH2(1-Me-4-NO2-pyrazol-5-yl) 490
    314 CO (CH2)2phenyl NH(2,4-F2—C6H3) 555
    315 CO H NH(2,4-Me2—C6H3) 422
    316 CO cPr NHCH2C6H5 468
    317 CO (CH2)2OCONHCH2phenyl NHCH2C6H5 605
    318 CO (CH2)2OH NHCH2C6H5 472
    319 CO (CH2)2F NHCH2C6H5 474
    320 CO cPr NHCH2(4-F—C6H4) 486
    321 CO (CH2)2OH NHCH2(4-F—C6H4) 490
    322 CO (CH2)2F NHCH2(4-F—C6H4) 492
    323 CO Et NHCH2(4-CF3—C6H4) 524
    324 CO Et NHCH2(thien-3-yl) 462
    325 CO Et NHCH2(indol-3-yl) 495
    326 CO Et NHCH2(5-OMe-indol-3-yl) 525
    327 CO Et NHCH2(2,5-F2—C6H3) 492
    328 CO Et NHCH2(3-Cl-4-OH—C6H3) 507
    329 CO Et NHCH2(thien2-yl) 462
    330 CO Et NHCH2(3-OMe—C6H4) 486
    331 CO Et NHCH2(2,6-F2—C6H3) 492
    332 CO Et NHCH2(3,5-F2—C6H3) 492
    333 CO Et NHCH2(2-F—C6H4) 474
    334 CO Et NHCH2(4-OCF3—C6H4) 540
    335 CO Et NHCH2(2,2-Me2-3-C(O)Me—cBu) 504
    336 CO Et NHCH2(2-phenyl-5-Me-oxazol-4-yl) 537
    337 CO Et NH(indazol-3-yl) 482
    338 CO Et NHCH2(4-S(O)2Me—C6H4) 534
    339 CO Et NHCH2(2-OMe—C6H4) 486
    340 CO Et NHCH2(3,5-Me2-isoxazol-4-yl) 475
    341 CO Et NHCH2(5-phenyl-[1,2,4]triazol-3-yl) 523
    342 CO Et NHCH2(5-CN-indol-3-yl) 520
    343 CO Et NHCH2(2,5-(OMe)2—C6H3) 516
    344 CO Et NHCH2(3-F—C6H4) 474
    345 CO Et NLICH2(3,4-(OMe)2—C6H3) 516
    346 CO Et NHCH2(3,4,5-(OMe)3—C6H4 546
    347 CO Et NHCH2(3-OH—C6H4) 472
    348 CO Et NHCH2(4-OH—C6H4) 472
    349 CO Et NHCH2-(3-F-4-OH—C6H3) 490
    350 CO Et NHCH2(3-OMe-4-OH—C6H3) 502
    351 CO Et NHCH2(4-NH2—C6H4) 471
    352 CO Et NHCH2(3,5-(OMe)2-4-OH—C6H2) 532
    353 CO Et NHCH2(3-NH2—C6H4) 471
    354 CO Me CH2(4-(S(O)2NH—cPr)—C6H4) 546
    355 CO Me CH2(4-(S(O)2NH-isoBu)-C6H4) 562
    356 CO Me CH2(4-(S(O)2NH(CH2)2OMe)—C6H4) 564
    357 CO Me CH2(4-(S(O)2NH(CH2)2OH)—C6H4) 550
    358 CO Me CH2(4-(S(O)2NHCH2C≡CH)—C6H4) 544
    359 CO Me CH3(4-(S(O)2NHCH2CH═CH2)— 546
    C6H4)
    360 CO Me CH2(4-(S(O)2NH(CH2)3OH)—C6H4) 564
    361 CO Me CH2(4-(S(O)2N(Me)CH2C≡CH)— 558
    C6H4)
    362 CO Me CH2(4-(S(O)2N(Me)CH2CH═CH2)— 560
    C6H4)
    363 CO Me CH2(4-(S(O)2N(Me)Et)—C6H4 548
    364 CO Me CH2-4-(S(O)2N(Me)(CH2)2OH)— 564
    C6H4)
    365 CO Me CH2(4-(S(O)2NHCH2—cPr)—C6H4) 560
    366 CO Me CH2(4-(S(O)2N(Me)isoPr)—C6H4) 562
    367 CO Me CH2(4-(S(O)2NHCH(Me)CH2OH)— 564
    C6H4)
    368 CO Me CH2(4-(S(O)2-azetidinyl)-C6H4) 546
    369 CO Me CH2(4-(S(O)2-pyrrolidinyl)-C6H4) 560
    370 CO Me CH2(4-(S(O)2-morpholin-4-yl)-C6H4) 576
    371 CO Me CH2(4-(S(O)2NH-isoPr)—C6H4) 548
    372 CO Me CH2(4-(S(O)2NHMe)—C6H4) 520
    373 CO Me CH2(4-(S(O)2NHCH2CH(Me)OH)— 564
    C6H4)
    374 CO Me CH2(4-(S(O)2-3-CH2OH-piperidin-1- 604
    yl)-C6H4)
    375 CO Me CH2(4-(S(O)2NH(CH2)2-imidazol-4- 600
    yl)-C6H4)
    376 CO Me CH2(4-(S(O)2-3-CH2OH-pyrrolidin- 590
    1-yl)-C6H4)
    377 CO Me CH2(4-(S(O)2-3-OH-piperidin-1-yl- 590
    C6H4)
    379 CO Me CH2(4-(S(O)2NH-pyridin-3-yl)-C6H4) 583
    380 CO Me CH2(4-(S(O)2NHCH2CN)—C6H4) 545
    381 CO Me CH2(4-(S(O)2-pyrrolen-1-yl)-C6H4) 558
    382 CO Me CH2(4-(S(O)2-4-OH-piperidin-1-yl)- 590
    C6H4)
    383 CO Me CH2(4-(S(O)2NH-pyrazo1-3yl)-C6H4) 572
    384 CO Me CH2(4-(S(O)2-3-OH-pyrrolidin-1-yl)- 576
    C6H4)
    385 CO Me CH2(4-(S(O)2NH(CH2)2OH)—C6H4) 514
    386 CO Me CH2(4-(S(O)2NH(CH2)3OH)—C6H4) 528
    387 CO Me CH2(4-(S(O)2NHCH2CH(OH)Me)— 528
    C6H4)
    388 CO Me NH(4-F—C6H4) 446
    389 CO Me NHCH(Me)phenyl 456
    390 CO H CH(CH2CH═CH2)-4-S(O)2Me—C6H4 531
    391 CO Me pyrrolidin-1yl 406
    392 CO H CH2(1,3-benzodioxol-5-yl) 395
    393 CO H CH2(4-NMe2—C6H4) 394
    394 CO H CH2(3-Cl-4-OH—C6H3) 402
    (404)
    395 CO H CH2(4-CO2Me—C6H4) 409
    396 CO H CH2(3-CN-4-OH—C6H3) 392
    397 CO H CH2(3-F-4-(thiomorphlin-4-yl)-C6H3) 470
    398 CO H CH2(3-OMe—C6H4) 381
    399 CO H CH2(3-OH—C6H4) 367
    400 CO H CH2(3-F-4-OH—C6H3) 384
    401 CO Et NHCH2(4-S(O)2Me—C6H4)
    402 CO Et NHCH2(4-S(O)2NH2—C6H4)
    403 CO Et CH2C6H5
    404 CO CH2CH═CH2 NHCH2(4-S(O)2Me—C6H4)
    405 CO CH2CH═CH2 NHCH2(4-S(O)2NH2—C6H4)
    406 CO CH2CH═CH2 CH2C6H5
    407 CO cPr NHCH2(4-S(O)2Me—C6H4)
    408 CO cPr NHCH2(4-S(O)2NH2—C6H4)
    409 CO cPr CH2C6H5
  • wherein the variables X, R[0085] 2 and R3 for each compound of Table II are the same as the correspondingly numbered compound in Table I. Mass Spectrum details are given for certain compounds of Table II.
    Example MS
    Number (MH+)
     38 451
     71 408
     79 366
     80 430
     81 386
     83 366
     86 411
     88 411
    103 445
    107 421
    108 432
    110 365
    111 433
    112 345
    115 391
    117 399
    118 433
    122 399
    123 399
    126 383
    127 395
    128 401
    129 371
    130 371
    131 404
    132 433
    133 401
    134 433
    135 449
    140 396
    140 (R) 396
    140 (S) 396
    143 (R) 385 (387)
    143 (S) 385 (387)
    144 400
    145 380
    147 366
    150 444
    151 400
    157 380
    160 414
    165 394
    166 445
    168 396
    189 414
    190 411
    191 420
    192 422
    193 381
    194 423
    195 467
    196 425
    197 447
    198 469
    199 439
    200 492
    201 420
    202 380
    203 431
    204 382
    205 434
    206 379
    207 365
    208 351
    209 395
    210 369
    211 393
    212 406
    213 365
    214 395
    215 408
    216 419
    217 427
    218 387
    219 435
    220 461
    221 437
    222 407
    223 430
    224 458
    225 419
    226 431
    227 429 (431)
    228 445
    229 450
    230 383
    231 402
    232 366
    237 411
    239 367
    240 419
    245 406
    392 395
    393 394
    394 402 (404)
    395 409
    396 392
    397 470
    398 381
    399 367
    400 384
  • [0086]
    TABLE IlI
    Table III discloses compounds of formula (Ic):
    (Ic)
    Figure US20040006081A1-20040108-C00008
    wherein the variables R1, X, R2 and R3 are as defined in the Table below.
    Mass Spectrum details are given for certain compounds of Table III.
    Compound No. R1 m X R2 R3 LCMS (MH+)
    1 CH2(2,6-(MeO)2—C6H3) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 510
    2 CH2(2-(4-NO2—C6H4)-fur-5-yl) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 561
    3 CH2(3-OH-4-NO2—C6H3) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 511
    4 CH2(2-Et-fur-5-yl) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 468
    5 CH2(3-Me—C6H4) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 463
    6 CH2(2,4-MeO2-pyrimidin-5-yl) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 512
    7 CH2(indol-3-yl) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 489
    8 CH2(1-phenyl-pyrrol-3-yl) 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 515
    9 (CH2)3phenyl 1 CO (CH2)2phenyl NH(2,4-F2—C6H3) 464
    10‡ iso-propyl 1 CO 4-Cl—C6H4 benzyl
    11 (CH2)2C(C6H5)(4-F—C6H4)OH 1 CO Et CH2(4-S(O)2Me—C6H4) 553
    12 (CH2)2CH(CH═CH2)C6H5 1 CO Me CH2(4-F—C6H4) 395
    13 (CH2)2CH(C6H5)azetidin-1-yl 1 CO Me CH2(4-F—C6H4) 424
    14 (CH2)2CH(C6H5)pyrrolidin-1-yl 1 CO Me CH2(4-F—C6H4) 438
    15 (CH2)2CH(C6H5)(4-F—C6H4) 1 CO Me CH2(4-F—C6H4) 463
    16 (CH2)2CH(4-F—C6H4)2 1 CO Me CH2(4-F—C6H4) 481
    17 (CH2)2CH(4-F—C6H4)2 1 CO Me CH2(4-S(O)2NH2—C6H4) 542
    18 (CH2)2N(C6H5)2 1 CO CH2CH═CH2 CH2(4-S(O)2Me—C6H4) 532
    19 (CH2)2N(C6H5)2 1 CO Me CH2(4-F—C6H4) 446
    20 (CH2)2N(C6H5)CO(CH2)2(4-OH— 1 CO Et CH2(4-S(O)2Me—C6H4) 591
    C6H4)
    21 (CH2)2N(C6H5)CO(2-SMe- 1 CO Et CH2(4-S(O)2Me—C6H4) 595
    pyridin-3-yl)
    22 (CH2)2N(C6H5)CO(2-OH-5-F— 1 CO Et CH2(4-S(O)2Me—C6H4) 580 (M-H)
    C6H3)
    23 (CH2)2CH(C6H5)NH2 1 CO Et CH2(4-S(O)2Me—C6H4) 458
    24 (CH2)2NHC6H5 1 CO Et CH2(4-S(O)2Me—C6H4) 444
    25 (CH2)2NHC6H5 1 CO Et CH2(4-F—C6H4) 384
    26 (CH2)2CH(OH)C6H5 1 CO Et CH2(4-S(O)2Me—C6H4) 459
    27 CH(Me)CH2CH(C6H5)2 1 CO Et CH2(4-S(O)2Me—C6H4) 533
    28 CH(Me)(CH2)2C6H5 1 CO Et CH2(4-S(O)2Me—C6H4) 457
    29 (CH2)2CH(Me)(3-CF3—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 525
    30 (CH2)2CH(Me)(3-Cl—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 491
    31 (CH2)2CH(Me)C6H5 1 CO Et CH2(4-S(O)2Me—C6H4) 457
    32 (CH2)2CH(Me)(3,4-Cl2—C6H3) 1 CO Et CH2(4-S(O)2Me—C6H4) 525
    33 (CH2)2CH(C6H5)2 0 CO Et CH2(4-S(O)2Me—C6H4) 477
    34 (CH2)2CH(4-Cl—C6H4)4-pyridyl 1 CO Et CH2(4-S(O)2Me—C6H4) 554
    35 (CH2)2CH(4-Cl—C6H4)2-pyridyl 1 CO Et CH2(4-S(O)2Me—C6H4) 554
    36 (CH2)2CH(C6H5)-(1,3- 1 CO Et CH2(4-S(O)2Me—C6H4) 563
    benzodioxol-5-yl)
    37 (CH2)2CH(C6H5)(4-Cl—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 553
    38 (CH2)2CH(C6115)(3,4-Cl2—C6H3) 1 CO Et CH2(4-S(O)2Me—C6H4) 587
    39 (CH2)2CH(C6H5)(4-MeO—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 549
    40 (CH2)2CH(C6H5)(3-Cl—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 553
    41 (CH2)2CH(C6H5)(4-Me—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 533
    42 (CH2)2CH(C6H5)(4-CF3—C6H4) 1 CO Et CH2(4-S(O)2Me—C6H4) 587
    43 (CH2)2CH(4-F—C6H4)2 1 CO Et CH2(4-S(O)2Me—C6H4) 555
    44 (CH2)2CH(4-F—C6H4)2 1 CO CH2CH═CH2 CH2(4-S(O)2Me—C6H4) 567
  • [0087]
    TABLE IV
    Table IV discloses compounds of formula (Id):
    (Id)
    Figure US20040006081A1-20040108-C00009
    wherein the variables R14, X, R2 and R3 are as defined in the Table below.
    Mass Spectrum details are given for certain compounds in Table IV.
    Compound LCMS
    No. X R2 R3 R14 (MH+)
    1 CO Et CH2(4-S(O)2Me—C6H4) phenyl 562
    2 CO Et CH2(4-S(O)2Me—C6H4) iso-Pr 528
    3 CO Et CH2(4-S(O)2Me—C6H4) CH(CH2CH3)2 556
    4 CO Et CH2(4-S(O)2Me—C6H4) CH(CH3)CH2CH2CH3 556
    5 CO Et CH2(4-S(O)2Me—C6H4) CH2C(CH3)3 556
    6 CO Et CH2(4-S(O)2Me—C6H4) CH2CH(CH3)2 542
    7 CO Et CH2(4-S(O)2Me—C6H4) CH2CH(CH3)CH2CH3 556
    8 CO Et CH2(4-S(O)2Me—C6H4) Et 514
    9 CO Et CH2(4-S(O)2Me—C6H4) CH2CH2CH(CH3)2 556
    10 CO Et CH2(4-S(O)2Me—C6H4) n-Pr 528
    11 CO Et CH2(4-S(O)2Me—C6H4) 1-Me-pyrrol-2-yl 565
    12 CO Et CH2(4-S(O)2Me—C6H4) furan-2-yl 552
    13 CO Et CH2(4-S(O)2Me—C6H4) tert-Bu 542
    14 CO Et CH2(4-S(O)2Me—C6H4) C(CH3)2CH2CH3 556
    15 CO Et CH2(4-S(O)2Me—C6H4) CH2OEt 544
    16 CO Et CH2(4-S(O)2Me—C6H4) n-Bu 542
    17 CO Et CH2(4-S(O)2Me—C6H4) n-pentyl 556
    18 CO Et CH2(4-S(O)2Me—C6H4) C(OH)Me2 544
    19 CO Et CH2(4-S(O)2Me—C6H4) pyrrol-2-yl 551
    20 CO Et CH2(4-S(O)2Me—C6H4) furan-3-yl 552
    21 CO Et CH2(4-S(O)2Me—C6H4) thien-2-yl 568
    22 CO Et CH2(4-S(O)2Me—C6H4) thien-3-yl 568
    23 CO Et CH2(4-S(O)2Me—C6H4) pyrazin-2-yl 564
    24 CO Et CH2(4-S(O)2Me—C6H4) pyridin-2-yl 563
    25 CO Et CH2(4-S(O)2Me—C6H4) pyridin-3-yl 563
    26 CO Et CH2(4-S(O)2Me—C6H4) pyridin-4-yl 563
    27 CO Et CH2(4-S(O)2Me—C6H4) 3-Me-furan-2-yl 566
    28 CO Et CH2(4-S(O)2Me—C6H4) CH2CH2OMe 544
    29 CO Et CH2(4-S(O)2Me—C6H4) CH2CH2OEt 558
    30 CO Et CH2(4-S(O)2Me—C6H4) CH(OH)CH2CH2CH3 558
    31 CO Et CH2(4-S(O)2Me—C6H4) 2-Me-furan-3-yl 566
    32 CO Et CH2(4-S(O)2Me—C6H4) 4-Me-oxazol-5-yl 567
    33 CO Et NHCH2C6H5 azetidin-1-yl
    34 CO Et NHCH2(4-F—C6H4) azetidin-1-yl
    35 CO Et NNCH2(4-S(O)2Me—C6H4) azetidin-1-yl
    36 CO Et NHCH2(4-S(O)2NH2—C6H4) azetidin-1-yl
    37 CO Et CH2C6H5 azetidin-1-yl
    38 CO Et CH2(4-F—C6H4) azetidin-1-yl
    39 CO Et CH2(4-S(O)2Me—C6H4) azetidin-1-yl
    40 CO Et CH2(4-S(O)2NH2C6H4) azetidin-1-yl
    41 CO allyl NHCH2C6H5 azetidin-1-yl
    42 CO allyl NHCH2(4-F—C6H4) azetidin-1-yl
    43 CO allyl NHCH2(4-S(O)2Me—C6H4) azetidin-1-yl
    44 CO allyl NHCH2(4-S(O)2NH2—C6H4) azetidin-1-yl
    45 CO allyl CH2C6H5 azetidin-1-yl
    46 CO allyl CH2(4-F—C6H4) azetidin-1-yl
    47 CO allyl CH2(4-S(O)2Me—C6H4) azetidin-1-yl
    48 CO allyl CH2(4-S(O)2NH2—C6H4) azetidin-1 -yl
    49 CO cPr NHCH2C6H5 azetidin-1-yl
    50 CO cPr NHCH2(4-F—C6H4) azetidin-1-yl
    51 CO cPr NHCH2(4-S(O)2Me—C6H4) azetidin-I-yl
    52 CO cPr NHCH2(4-S(O)2NH2—C6H4) azetidin-1-yl
    53 CO cPr CH2C6H5 azetidin-1-yl
    54 CO cPr CH2(4-F—C6H4) azetidin-1-yl
    55 CO cPr CH2(4-S(O)2Me—C6H4) azetidin-1-yl
    56 CO cPr CH2(4-S(O)2NH2—C6H4) azetidin-1-yl
    57 CO Et CH2(4-S(O)2Me—C6H4) 2-F—C6H4 580
    58 CO Et CH2(4-S(O)2Me—C6H4) 2,6-F2—C6H3 598
    59 CO Et CH2(4-S(O)2Me—C6H4) 2-Cl—C6H4 596
    60 CO Et CH2(4-S(O)2Me—C6H4) 2-MeO—C6H4 592
    61 CO Et CH2(4-S(O)2Me—C6H4) 3-CN—C6H4 587
    62 CO Et CH2(4-S(O)2Me—C6H4) 3-F—C6H4 580
    63 CO Et CH2(4-S(O)2Me—C6H4) 3-MeO—C6H4 592
    64 CO Et CH2(4-S(O)2Me—C6H4) 3-Me—C6H4 576
    65 CO Et CH2(4-S(O)2Me—C6H4) 4-CN—C6H4 587
    66 CO Et CH2(4-S(O)2Me—C6H4) 4-F—C6H4 580
    67 CO Et CH2(4-S(O)2Me—C6H4) 4-Cl—C6H4 596
    68 CO Et CH2(4-S(O)2Me—C6H4) 4-(COCH3)C6H4 604
    69 CO Et CH2(4-S(O)2Me—C6H4) 4-Me—C6H4 576
    70 CO Et CH2(4-S(O)2Me—C6H4) CH(Me)C6H5 590
    71 CO Et CH2(4-S(O)2Me—C6H4) CH2(2-F—C6H4) 594
    72 CO Et CH2(4-S(O)2Me—C6H4) CH2(2-MeO—C6H4) 606
    73 CO Et CH2(4-S(O)2Me—C6H4) CH2(3-MeO—C6H4) 606
    74 CO Et CH2(4-S(O)2Me—C6H4) CH2(4-F—C6H4) 594
    75 CO Et CH2(4-S(O)2Me—C6H4) CH2(4-MeO—C6H4) 606
    76 CO Et CH2(4-S(O)2Me—C6H4) indol-5-yl 601
    77 CO Et CH2(4-S(O)2Me—C6H4) 6-Cl-pyridin-3-yl 597
    78 CO Et CH2(4-S(O)2Me—C6H4) 2-NO2—C6H4 607
    79 CO Et CH2(4-S(O)2Me—C6H4) 3-NO2—C6H4 607
    80 CO Et CH2(4-S(O)2Me—C6H4) 4-NO2—C6H4 607
    81 CO Et CH2(4-S(O)2Me—C6H4) 3,4-F2—C6H3 598
    82 CO Et CH2(4-S(O)2Me—C6H4) benztriazol-4-yl 603
    83 CO Et CH2(4-S(O)2Me—C6H4) 2-Me-pyridin-3-yl 577
    84 CO Et CH2(4-S(O)2Me—C6H4) 6-Me-pyridin-2-yl 577
    85 CO Et CH2(4-S(O)2Me—C6H4) CH(OMe)C6H5 606
    86 CO Et CH2(4-S(O)2Me—C6H4) 5-Me-pyrazin-2-yl 578
    87 CO Et CH2(4-S(O)2Me—C6H4) dihydrobenzofuran-4-yl 604
    88 CO Et CH2(4-S(O)2Me—C6H4) 2-OMe-pyridin-3-yl 593
    89 CO Et CH2(4-S(O)2Me—C6H4) 6-Cl-pyridin-2-yl 597
    90 CO Et CH2(4-S(O)2Me—C6H4) 2-Cl-pyridin-4-yl 597
    91 CO Et CH2(4-S(O)2Me—C6H4) 1H-pyridin-2-on-6-yl 579
    92 CO Et CH2(4-S(O)2Me—C6H4) indol-7-yl 601
    93 CO Et CH2(4-S(O)2Me—C6H4) dihydrobenzofuran-7-yl 604
    94 CO Et CH2(4-S(O)2Me—C6H4) 6-CN-pyridin-3-yl 588
    95 CO Et CH2(4-S(O)2Me—C6H4) 2-F-pyridin-3-yl 581
  • The following abbreviations are used in Tables I to IV: [0088]
    Me = methyl Et = ethyl
    Pr = propyl Bu = butyl
    cPr = cyclopropyl cBu = cyclobutyl
  • The compounds of formula (I), (Ia), (Ib), (Ic) or (Id) can be prepared as shown in the processes on pages marked Schemes 1 to 14 below. (In Scheme 10 suitable coupling agents include HATU (O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate) and PyBROP (bromo-tris-pyrrolidinophosphonium hexafluorophosphate) which may be employed according to Example 26.) The starting materials for these processes are either commercially available or can be prepared either by literature methods or by adapting literature methods. In the Schemes the variables R[0089] 1*, R2* and R3* have been used where the group R1, R2 or R3 is, respectively, CH2R1*, CH2R2* or CH2R3*; Ac is CH3C(O); and Ar1 and Ar2 denote aromatic rings which are optionally substituted. Although Schemes 1-14 are depicted for m and p=1, and R4, R5, R6 and R7 as hydrogen, it is clear that they can be readily adapted for alternative values of m, p, R4, R5, R6 and R7.
  • In a further aspect the invention provides processes for preparing the compounds of formula (I), (Ia), (Ib), (Ic) and (Id). Many of the intermediates in the processes are novel and these are provided as further features of the invention. [0090]
  • The compounds of the invention have activity as pharmaceuticals, in particular as modulators (such as agonists, partial agonists, inverse agonists or antagonists) of chemokine receptor (especially CCR5) activity, and may be used in the treatment of autoimmune, inflammatory, proliferative or hyperproliferative diseases, or immunologically-mediated diseases (including rejection of transplanted organs or tissues and Acquired Immunodeficiency Syndrome (AIDS)). Examples of these conditions are: [0091]
  • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); pulmonary fibrosis; asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthmia (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia; [0092]
  • (2) (bone and joints) artbrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behcet's disease, Sjogren's syndrome or systemic sclerosis; [0093]
  • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; [0094]
  • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); [0095]
  • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or [0096]
  • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, inhibiting the entry of viruses into target cells, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura, disorders of the menstrual cycle, glomerulonephritis or cerebral malaria. [0097]
  • The compounds of the present invention are also of value in inhibiting the entry of viruses (such as human immunodeficiency virus (HIV)) into target calls and, therefore, are of value in the prevention of infection by viruses (such as HIV), the treatment of infection by viruses (such as HIV) and the prevention and/or treatment of acquired immune deficiency syndrome (AIDS). [0098]
  • According to a further feature of the invention there is provided a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use in a method of treatment of a warm blooded animal (such as man) by therapy (including prophylaxis). [0099]
  • According to a further feature of the present invention there is provided a method for modulating chemokine receptor activity (especially CCR5 receptor activity) in a warm blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof or a solvate thereof. [0100]
  • The present invention also provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, as a medicament, especially a medicament for the treatment of transplant rejection, respiratory disease, psoriasis or rheumatoid arthritis (especially rheumatoid arthritis). [Respiratory disease is, for example, COPD, asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)} or rhinitis {acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis}; and is particularly asthma or rhinitis]. [0101]
  • In another aspect the present invention provides the use of a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man). [0102]
  • The invention also provides a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof, for use as a medicament, especially a medicament for the treatment of rheumatoid arthritis. [0103]
  • In another aspect the present invention provides the use of a compound of the formula (I), (Ia), (Ib) or (Ic), or a pharmaceutically acceptable salt thereof or a solvate thereof, in the manufacture of a medicament for use in therapy (for example modulating chemokine receptor activity (especially CCR5 receptor activity (especially rheumatoid arthritis)) in a warm blooded animal, such as man). [0104]
  • The invention further provides the use of a compound of formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of: [0105]
  • (1) (the respiratory tract) obstructive diseases of airways including: chronic obstructive pulmonary disease (COPD) (such as irreversible COPD); asthma {such as bronchial, allergic, intrinsic, extrinsic or dust asthma, particularly chronic or inveterate asthma (for example late asthma or airways hyper-responsiveness)}; bronchitis {such as eosinophilic bronchitis}; acute, allergic, atrophic rhinitis or chronic rhinitis including rhinitis caseosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca or rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous or pseudomembranous rhinitis or scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) or vasomotor rhinitis; sarcoidosis; farmer's lung and related diseases; nasal polyposis; fibroid lung or idiopathic interstitial pneumonia; [0106]
  • (2) (bone and joints) arthrides including rheumatic, infectious, autoimmune, seronegative spondyloarthropathies (such as ankylosing spondylitis, psoriatic arthritis or Reiter's disease), Behget's disease, Sjogren's syndrome or systemic sclerosis; [0107]
  • (3) (skin and eyes) psoriasis, atopic dermatitis, contact dermatitis or other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Phemphigus, bullous Phemphigus, Epidermolysis bullosa, urticaria, angiodermas, vasculitides erythemas, cutaneous eosinophilias, uveitis, Alopecia areata or vernal conjunctivitis; [0108]
  • (4) (gastrointestinal tract) Coeliac disease, proctitis, eosinophilic gastro-enteritis, mastocytosis, Crohn's disease, ulcerative colitis, irritable bowel disease or food-related allergies which have effects remote from the gut (for example migraine, rhinitis or eczema); [0109]
  • (5) (Allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea; or chronic graft versus host disease; and/or [0110]
  • (6) (other tissues or diseases) Alzheimer's disease, multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), Lupus disorders (such as lupus erythematosus or systemic lupus), erythematosus, Hashimoto's thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, leprosy (such as lepromatous leprosy), Peridontal disease, Sezary syndrome, idiopathic thrombocytopenia pupura or disorders of the menstrual cycle; [0111]
  • in a warm blooded animal, such as man. [0112]
  • The present invention further provides a method of treating a chemokine mediated disease state (especially a CCR5 mediated disease state) in a warm blooded animal, such as man, which comprises administering to a mammal in need of such treatment an effective amount of a compound of formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or solvate thereof. [0113]
  • In order to use a compound of the invention, or a pharmaceutically acceptable salt thereof or solvate thereof, for the therapeutic treatment of a warm blooded animal, such as man, in particular modulating chemokine receptor (for example CCR5 receptor) activity, said ingredient is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition. [0114]
  • Therefore in another aspect the present invention provides a pharmaceutical composition which comprises a compound of the formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvate thereof (active ingredient), and a pharmaceutically acceptable adjuvant, diluent or carrier. In a further aspect the present invention provides a process for the preparation of said composition which comprises mixing active ingredient with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition. [0115]
  • The pharmaceutical compositions of this invention may be administered in standard manner for the disease condition that it is desired to treat, for example by topical (such as to the lung and/or airways or to the skin), oral, rectal or parenteral administration. For these purposes the compounds of this invention may be formulated by means known in the art into the form of, for example, aerosols, dry powder formulations, tablets, capsules, syrups, powders, granules, aqueous or oily solutions or suspensions, (lipid) emulsions, dispersible powders, suppositories, ointments, creams, drops and sterile injectable aqueous or oily solutions or suspensions. [0116]
  • A suitable pharmaceutical composition of this invention is one suitable for oral administration in unit dosage form, for example a tablet or capsule which contains between 0.1 mg and 1 g of active ingredient. [0117]
  • In another aspect a pharmaceutical composition of the invention is one suitable for intravenous, subcutaneous or intramuscular injection. [0118]
  • Each patient may receive, for example, an intravenous, subcutaneous or intramuscular dose of 0.01 mgkg[0119] −1 to 100 mgkg−7 of the compound, preferably in the range of 0.1 mgkg−1 to 20 mgkg−1 of this invention, the composition being administered 1 to 4 times per day. The intravenous, subcutaneous and intramuscular dose may be given by means of a bolus injection. Alternatively the intravenous dose may be given by continuous infusion over a period of time. Alternatively each patient will receive a daily oral dose which is approximately equivalent to the daily parenteral dose, the composition being administered 1 to 4 times per day.
  • The following illustrate representative pharmaceutical dosage forms containing the compound of formula (I), (Ia), (Ib), (Ic) or (Id), or a pharmaceutically acceptable salt thereof or a solvent thereof (hereafter Compound X), for therapeutic or prophylactic use in humans: [0120]
    (a)
    Tablet I mg/tablet
    Compound X 100
    Lactose Ph. Eur. 179
    Croscarmellose sodium 12.0
    Polyvinylpyrrolidone 6
    Magnesium stearate 3.0
  • [0121]
    (b)
    Tablet II mg/tablet
    Compound X 50
    Lactose Ph. Eur. 229
    Croscarmellose sodium 12.0
    Polyvinylpyrrolidone 6
    Magnesium stearate 3.0
  • [0122]
    (c)
    Tablet III mg/tablet
    Compound X 1.0
    Lactose Ph. Eur. 92
    Croscarmellose sodium 4.0
    Polyvinylpyrrolidone 2.0
    Magnesium stearate 1.0
  • [0123]
    (d)
    Capsule mg/capsule
    Compound X 10
    Lactose Ph. Eur. 389
    Croscarmellose sodium 100
    Magnesium stearate 1.0
  • [0124]
    (e)
    Injection I (50 mg/ml)
    Compound X 5.0% w/v
    Isotonic aqueous solution to 100%
  • Buffers, pharmaceutically-acceptable cosolvents such as polyethylene glycol, polypropylene glycol, glycerol or ethanol or complexing agents such as hydroxy-propyl β-cyclodextrin may be used to aid formulation. [0125]
  • The above formulations may be obtained by conventional procedures well known in the pharmaceutical art. The tablets (a)-(c) may be enteric coated by conventional means, for example to provide a coating of cellulose acetate phthalate. [0126]
  • The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise: [0127]
  • (i) temperatures are given in degrees Celsius (° C.); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25° C.; [0128]
  • (ii) organic solutions were dried over anhydrous magnesium sulphate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mm Hg) with a bath temperature of up to 60° C.; [0129]
  • (iii) chromatography unless otherwise stated means flash chromatography on silica gel; thin layer chromatography (TLC) was carried out on silica gel plates; where a “Bond Elut” column is referred to, this means a column containing 10 g or 20 g of silica of 40 micron particle size, the silica being contained in a 60 ml disposable syringe and supported by a porous disc, obtained from Varian, Harbor City, Calif., USA under the name “Mega Bond Elut SI”. Where an “Isolute™ SCX column” is referred to, this means a column containing benzenesulphonic acid (non-endcapped) obtained from International Sorbent Technology Ltd., 1st House, Duffryn Industial Estate, Ystrad Mynach, Hengoed, Mid Clamorgan, UK. Where “Argonaut™ PS-tris-amine scavenger resin” is referred to, this means a tris-(2-aminoethyl)amine polystyrene resin obtained from Argonaut Technologies Inc., 887 Industrial Road, Suite G, San Carlos, Calif., USA. [0130]
  • (iv) in general, the course of reactions was followed by TLC and reaction times are given for illustration only; [0131]
  • (v) yields, when given, are for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required; [0132]
  • (vi) when given, [0133] 1H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio DMSO (CD3SOCD3) as the solvent unless otherwise stated; coupling constants (J) are given in Hz;
  • (vii) chemical symbols have their usual meanings; SI units and symbols are used; [0134]
  • (viii) solvent ratios are given in percentage by volume; [0135]
  • (ix) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (APCI) mode using a direct exposure probe; where indicated ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion—(M+H)[0136] +;
  • (x) LCMS characterisation was performed using a pair of Gilson 306 pumps with Gilson 233 XL sampler and Waters ZMD4000 mass spectrometer. The LC comprised water symmetry 4.6×50 column C18 with 5 micron particle size. The eluents were: A, water with 0.05% formic acid and B, acetonitrile with 0.05% formic acid. The eluent gradient went from 95% A to 95% B in 6 minutes. Where indicated ionisation was effected by electrospray (ES); where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion—(M+H)[0137] + and
  • (xi) the following abbreviations are used: [0138]
    DMSO dimethyl sulphoxide;
    DMF N-dimethylformamide;
    DCM dichloromethane;
    THF tetrahdydrofuran;
    DIPEA N,N-diisopropylethylamine;
    NMP N-methylpyrrolidinone;
    HATU O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium
    hexafluorophosphate;
    Boc tert-butoxycarbonyl
    MeOH methanol;
    EtOH ethanol; and
    EtOAc ethyl acetate.
    • EXAMPLE 1
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methylisonicotinamide (Compound No. 1 of Table I). [0139]
  • To a solution of isonicotinic acid (0.6 mg, 5 μM) in NMP (50 μL) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride (Method A) (1.9 mg, 5 μM) and diisopropylethylamine (8 μL, 45 μM) in NMP (50 μL) followed by a solution of bromo-tris-pyrrolidinophosphonium hexafluorophosphate (4.7 mg, 10 μM) in NMP (100 μL). After 15 h the reaction mixture was concentrated to give the title compound which was characterised by LCMS; MS: 415. [0140]
  • The method of Example 1 can be repeated using different acids in place of isonicotinic acid, or different piperidines (such as 4-methylamino-1-(3-R/S-phenylbutyl)piperidine dihydrochloride (Method B), 4-propargylamino-1-(3-R/S-phenylbutyl)piperidine (Method C), 4-allylamino-1-(3,3-diphenylpropyl)piperidine (Method D), 4-allylamino-1-(3-R/S-phenylbutyl)piperidine (Method E) or 4-(cyclopropylmethyl)amino-1-(3-R/S-phenylbutyl)piperidine (Method R)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride. [0141]
    • EXAMPLE 2
  • This Example illustrates the preparation of N′-(2,4-difluorophenyl)-N-[1-(2,6-dimethoxybenzyl)piperidin-4-yl]-N-phemethylurea (Compound No. 1 of Table III). [0142]
  • To a solution of 2,6-dimethoxybenzaldehyde (1.7 mg, 10 μM) in NMP (100 μL) was added a solution of 4-piperidinyl-N-(2-phenylethyl)-2,4-difluorophenylurea.trifluoroacetic acid (Method F) (2.4 mg, 5 μM) and diisopropylethylamine (1 μL, 5.5 μM) in NMP (100 μL). After 1.5 h a solution of sodium triacetoxyborohydride (2.8 mg, 15 μM) in acetonitrile: NMP, 1:1 (100 μL) was added. After 16 h at room temperature the reaction mixture was concentrated to give the title compound which was characterised by LCMS; MS: 510. [0143]
  • The procedure described in Example 2 can be repeated using different aldehydes in place of 2,6-dimethoxybenzaldehyde or other piperidines (such as 4-methylamino-1-(3,3-diphenylpropyl)piperidine.dihydrochloric acid (Method A) or 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-piperidinyl-N-(2-phenylethyl)-2,4-difluorophenylurea trifluoroacetic acid. [0144]
    • EXAMPLE 3
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-piperidin4-yl]-N-methyl-2-(trifluoromethoxy)benzenesulphonamide (Compound No. 53 of Table I). [0145]
  • To a solution of 2-trifluoromethoxybenzenesulphonyl chloride (1.3 mg, 5 μM) in acetonitrile (50 μL) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)-piperidine.dihydrochloride (Method A) (1.9 mg, 5 μM) and N,N-diisopropylethylamine (1.8 μL, 10 μM) in pyridine (50 μL). After 15 h the reaction mixture was concentrated to give the title compound which was characterised by LCMS; MS: 533. [0146]
  • The procedure described in Example 3 can be repeated using different sulphonylchlorides (such as 4-acetamido,3-chlorobenzenesulphonyl chloride) in place of 2-trifluoromethoxybenzenesulphonyl chloride or different piperidines (such as 4amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride. [0147]
    • EXAMPLE 4
  • This Example illustrates the preparation of N′-(3,4-dichlorophenyl)-N-[1-(3,3-diphenylpropyl)piperidin-4-yl]-N-methylurea (Compound No. 68 of Table I). [0148]
  • A solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine.dihydrochloride (Method A) (1.9 mg, 5 μM) and DIPEA (1.8 μL, 10 μM) in DCM (100 μL) was added to 3,4-dichlorophenylisocyanate (19 mg, 0.1 mM). After 15 h DCM (800 μL) was added and Argonaut™ PS-tris-amine scavenger resin (0.66 g) was added and the reaction mixture agitated. The resin swelled considerably and the mixture was left to stand in order for the DCM to evaporate. Methanol (0.5 ml) was added and the mixture agitated; the organic layer was then transferred to another vessel and concentrated to give the title compound as an oil, which was characterised by LCMS; MS: 496. [0149]
  • The procedure described in Example 4 can be repeated using various isocyanates or carbamoyl chlorides in place of 3,4-dichlorophenylisocyanate or other piperidines (such as 4-amino-1-(3,3-diphenylpropyl)piperidine.ditrifluoroacetic acid (Method G), 4-amino-1-(3-R/S-phenylbutyl)piperidine ditrifluoroacetic acid salt (Method H)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride. [0150]
    • EXAMPLE 5
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-piperidin-4-yl]-N-methylthiophene-2-carboxamide (Compound No. 96 of Table I). [0151]
  • A solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine (the free base of the compound described in Method A) (0.1 g, 0.32 mmol) in dichloromethane (4.0 ml) was added to 2-thiophene carboxylic acid (1.0 mmol). To the resulting mixture was added a solution of diisopropylcarbodiimide (0.15 ml, 1.0 mmol) in dichloromethane (1.0 ml) followed by a solution of 1-hydroxybenzotriazole (0.135 g, 1.0 mmol) in DMF (2.0 ml) and the resulting mixture stirred at ambient temperature for 18 hours. The reaction mixture was then applied to an ISOLUTE™ SCX column (5 g) which was then washed with MeOH (30 ml) followed by a 1:4 mixture of aqueous ammonia and methanol (30 ml). Evaporation of the final wash gave the title compound as an oil (101 mg, 75% yield); MS: 419. [0152]
  • The procedure described in Example 5 can be repeated using different carboxylic acids in place of 2-thiophene carboxylic acid or other piperidines (such as 4-amino-1-(3,3-diphenylpropyl)piperidine (free base from Method G), 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B) or 4-amino-1-(3-R/S-phenylbutyl)piperidine (free base from Method H)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine. [0153]
    • EXAMPLE 6
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-(N-methyl)-3-chlorophenylurea (Compound 144 of Table I). [0154]
  • A solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine (the free base of the compound described in Method A) (0.1 g; 0.32 mmol) in DCM (4.0 ml) was added to 3-chlorophenyl isocyanate (1.0 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then applied to an ISOLUTE™ SCX column (5 g) which was then washed with methanol (30 ml) followed by a 1:4 mixture of aqueous ammonia and MeOH (30 ml). Evaporation of the final wash gave the product as an oil (112 mg, 76% yield); MS: 462. [0155]
  • The procedure described in Example 6 can be repeated using different isocyanates or carbamoyl chlorides in place of 3-chlorophenylisocyanate or other piperidines (such as 4-methylamino-1-(3-R/S-phenylbutyl)piperidine (free base from Method B)) in place of 4-methylamino-1-(3,3-diphenylpropyl)piperidine. [0156]
    • EXAMPLE 7
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-4-(phenylmethoxy)phenylacetamide (Compound No. 268 of Table I). [0157]
  • To a solution of 4-methoxyphenylacetic acid (0.8 mg, 511 mol) in NMP (50 μL) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine dihydrochloride (Method A) (1.9 mg, 5 μmol) and DIPEA (8 μL, 45 μmol) in NMP (50 μL) followed by a solution of bromo-tris-pyrrolidino-phosphonium hexafluorophosphate (4.7 mg, 10 μmol) in NMP (100 μL). After 15 h the reaction mixture was concentrated to give the title compound which was characterised by LCMS; MS: 533. [0158]
    • EXAMPLE 8
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-allyl-4-fluorophenylacetamide (Compound No. 269 of Table I). [0159]
  • To 4-fluorophenylacetic acid (1 mmol) was added 4-allylamino-1-(3,3-diphenylpropyl)piperidine (0.1 g; 0.3 mmol) in dichloromethane (2 ml). A solution of 1-hydroxybenztiazole (0.135 g; 0.1 mmol) in DMF (2 ml) and di-isopropyl-carbodiimide (0.126 ml; 1 mmol) in DCM was then added. The resulting mixture was stirred at room temperature overnight. The mixture was then applied to an ISOLUTE™ SCX cartridge (5 g) and washed with methanol (30 ml). The product was then eluted with 15% methylamine in ethanol. Purification was achieved by BondElut chromatography eluting with a solvent mixture of DCM to 5% methanol in DCM yielding the title compound (72 mg, 50%), which was characterised by LCMS; MS: 471. [0160]
    • EXAMPLE 9
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-ethyl-4-trifluoromethoxyphenylacetamide (Compound No. 282 of Table I). [0161]
  • To a solution of 4-trifluoromethoxyphenylacetic acid (188 mg, 0.92 mmol) in dichloromethane (2 ml) was added 1-hydroxybenztriazole (124 mg) followed by diisopropylcarbodiimide (0.14 ml) and DMF (1 ml). The mixture was stirred at room temperature for 1 h, then a solution of 4-ethylamino-1-(3,3-diphenylpropyl)piperidine (147 mg, 0.46 mmol) in dichloromethane (2 ml) was added. The resulting mixture was stirred overnight then purified by eluting through an ISOLUTE™ SCX column with methanol followed by 2% aqueous ammonia in methanol. The product was then dissolved in ethyl acetate (2 ml) and treated with 1M HCl in diethyl ether (4 ml) giving the hydrochloride salt which was isolated by filtration, yielding N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-ethyl-4-trifluoromethoxyphenylacetamide hydrochloride as a foam, 210 mg, 87%; NMR: 1.1 (m,3H), 1.7 (m, 2H), 2.1 (m, 2H), 3.0 (m, 4H), 3.5 (m, 5H), 3.8 (m, 4H), 4.3 (m, 1H), 7.1 (m, 2H), 7.3 (m, 12H); MS: 525. [0162]
    • EXAMPLE 10
  • This Example illustrates the preparation of N′-(4-fluorophenylmethyl)-N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methylurea (Compound No. 388 of Table I). [0163]
  • To 4-fluorophenyl isocyanate (0.75 mmol) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine (0.19 g; 0.5 mmol) in DCM (4 ml). The resulting mixture was stirred at room temperature overnight. The resulting reaction mixture was then applied to an ISOLUTE™ SCX cartridge (5 g) and washed with methanol (30 ml). The product was then eluted using a 4:1 mixture of methanol and aqueous ammonia. Purification was achieved by BondElut chromatography eluting with a solvent mixture of DCM to 5% methanol in DCM to give the title compound (26 mg, 11%) which was characterised by LCMS; MS: 446. [0164]
    • EXAMPLE 11
  • This Example illustrates the preparation of N′-(2,4-difluorophenyl)-N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-phemethylurea (Compound No. 314 of Table I). [0165]
  • To a solution of N′-(2,4-difluorophenyl)-N-(4-piperidinyl)-N-phemethylurea trifluoroacetic acid salt (300 mg, 0.63 mmol) in DMF (5 ml) was added 3,3-diphenyl-1-bromopropane (360 mg, 1.26 mmol) followed by DIPEA (0.442 ml, 2.52 mmol). The resulting mixture was stirred at room temperature for 24 h. The reaction mixture was partitioned between water and dichloromethane, the organic phase was washed with water, dried (MgSO[0166] 4) and concentrated. The residue was purified by eluting through a silica gel cartridge with ethyl acetate followed by 5% ethanol in ethyl acetate to give the title compound as a gum, 80 mg; NMR: 1.6 (m, 6H), 4.9 (m, 5H), 2.2 (m, 3H), 2.8 (m, 3H), 3.9 (m, 2H), 7.0 (m, 1H), 7.2 (m, 15H), 7.4 (m, 1H), 8.0 (s, 1H); MS: 554.
    • EXAMPLE 12
  • This Example illustrates the preparation of N′-(4-trifluoromethylphenylmethyl)-N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-ethylurea (Compound No. 323 of Table I). [0167]
  • A solution of 4-trifluoromethylphenylacetic acid (0.8 mmol) in dry THF (2.0 ml) was cooled to 0° C. and triethylamine (0.11 ml; 0.8 mmol) in THF (1.0 ml) and diphenylphosphorylazide (0.17 ml; 0.8 mmol) in THF (2 ml) were added. Stirring was continued for 30 min. The mixture was allowed to warm to ambient temperature before toluene (5 ml) was added and the mixture heated to 100° C. for 1 h. After cooling to room temperature, a solution of4-ethylamino-1-(3,3-diphenylpropyl)piperidine (0.2 g; 0.6 mmol) in ethyl acetate (2 ml) was added and the mixture allowed to stir at room temperature for 72 h. The reaction mixture was then washed with aq. NaHCO[0168] 3 solution, dried and evaporated. Purification was by passage through a BondElut cartridge (Si) eluting with a gradient from 0-5% methanol in DCM, yielding the title compound (153 mg, 49%) which was characterised by LCMS; MS: 524.
    • EXAMPLE 13
  • This Example illustrates the preparation of pyrrolidine carboxylic acid N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl amide (Compound No. 391 of Table I). [0169]
  • To diethylcarbamoyl chloride (0.75 mmol) was added a solution of 4-methylamino-1-(3,3-diphenylpropyl)piperidine (0.19 g; 0.5 mmol) in DCM (4 ml) followed by triethylamine (0.14 ml; 1 mmol). The resulting mixture was stirred at room temperature overnight. The resulting reation mixture was then applied to an ISOLUTE™ SCX cartridge (5 g) and washed with methanol (30 ml). The product was then eluted using a 4:1 mixture of methanol and 0.88 aqueous ammonia. Purification was achieved by BondElut chromatography eluting with a solvent mixture of DCM to 5% methanol in DCM to give the product (79 mg, 39%) which was characterised by LCMS; MS: 406. [0170]
    • EXAMPLE 14
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-4-(cyclopropylaminosulfonyl)phenylacetamide (Compound No. 354 of Table I). [0171]
  • N-[1-(3,3-Diphenylpropyl)-4-piperidinyl]-N-methyl-4-fluorosulfonylphenylacetamide (0.005 mmol, in 100 μL MeCN) and cyclopropylamine (0.01 mmol in 100 μL MeCN) were mixed and allowed to stand overnight. The solvent was then evaporated to dryness under Genevac high vacuum. [0172]
    • EXAMPLE 15
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-4-(2-hydroxyethylaminocarbonyl)phenylacetamide hydrochloride (Compound No. 385 of Table I). [0173]
  • A mixture of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-4-methoxycarbonylphenylacetaride (0.1 g; 0.2 mmol) was heated at 60° C. in a mixture of ethanolamine (1.0 mL) and acetonitrile (1.0 mL) for 12 hours. After cooling the mixture was partitioned between ethyl acetate (5 mL) and water (8 mL). The organic layer was washed a further twice with water and dried (Na[0174] 2SO4) before purification on a silica BondElut, eluting with a gradient from 5-25% methanol in dichloromethane. The purified product was dissolved in ethyl acetate and treated with HCl in diethyl ether before evaporation to give the title compound as a solid (68 mg, 62%) which was characterised by LC-MS; MS: 514.
    • EXAMPLE 16
  • This Example illustrates the preparation of 4(2-[4-methanesulfonylphenyl])-pentenoic acid N-[1-(3,3-diphenylpropyl)4-piperidinyl]amide hydrochloride salt (Compound No. 390 of Table I). [0175]
  • To a cooled (5° C.) solution of N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-4-methanesulfonylphenylacetamide (1.61 g, 3.28 mmol) in DMF (1 mL) was added sodium hydride (131 mg 60% dispersion, 3.6 mmol). The resulting mixture was stirred for 5 minutes before the addition of allyl bromide (0.3 mL, 3.44 mmol). The reaction mixture was stirred at room temperature for 2 h then quenched with water. The mixture was extracted twice with ethyl acetate and the combined organic extracts were washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography (eluent 3% MeOH in DCM). The crude product was treated with ethereal HCl to afford the title compound (0.902 g); NMR (CDCl[0176] 3): 1.2 (m, 2H), 1.9 (m, 2H), 2.1 (m, 2H), 2.3 (m, 4H), 2.5 (m, 1H), 2.8 (m, 3H), 3.0 (s, 3H), 3.4 (m, 1H), 3.8 (m, 1H), 4.0 (dd, 1H), 5.1 (m, 2H), 5.4 (d, 1H, 5.7 (m, 1H), 7.2 (m, 10H), 7.6 (d, 2H), 7.9 (d, 2H); MS: 531.
    • EXAMPLE 17
  • This Example illustrates the preparation of N′-phenylmethyl-N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-allylurea (Compound No. 245 of Table II). [0177]
  • 3-Phenylbutyraldehyde (0.2 g, 1.36 mmol) was added to a solution of N′-phenylmethyl-N-[piperidin-4-yl]-N-allylurea hydrochloride (370 mg, 1.36 mmol) in methanol (20 ml). After 15 mins sodium triacetoxyborohydride (430 mg, 2.0 mmol) was added portionwise over 15 mins and the reaction was left to stir for 16 h. Water (5 ml) was added to the mixture and the methanol was removed in vacuo. The solution was diluted with water (30 ml), and partitioned with EtOAc (2×40 ml). The organic fractions were combined and washed with brine (30 ml), dried (MgSO[0178] 4) and concentrated. The oil was dissolved in MeOH (5 ml) and then applied to an ISOLUTE™ SCX column (5 g) which was then washed with MeOH (30 ml) followed by a 1:4 mixture of aqueous ammonia and methanol (30 ml). Addition of ethereal HCl to the final wash, followed by evaporation gave the title compound as a gum (152 mg, 0.38 mmol); MS: 406.
    • EXAMPLE 18
  • This Example illustrates the preparation of N-[1-(3-phenyl-3-[4fluorophenyl]-3-hydroxypropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 11 of Table III). [0179]
  • To a solution of N-[1-(3-[4-fluorophenyl]-3-oxopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide hydrochloride (470 mg, 0.92 mmol) in THF (40 mL) under an inert atmosphere was added phenylmagnesium bromide (10 mL, 1 M in THF) at room temperature. After stirring for 1 h saturated aqueous sodium bicarbonate solution was added and the resulting mixture was extracted with ethyl acetate. The organic phase was dried (MgSO[0180] 4) and concentrated. The title compound was obtained by silica column chromatography, eluting with 10% methanol in ethyl acetate yielding 120 mg. NMR (CDCl3): 1.18 and 1.23 (t, 3H), 1.65 (m, 2H), 1.84 (m, 2H), 2.42 (m, 2H), 3.02 (s, 3H), 3.35 (m, 2H), 3.65 (m, 4H), 3.68 and 3.78 (s, 2H), 4.73 (t, 2H), 6.97 (m, 2H), 7.2-7.4 (m, 9H), 7.90 (d, 2H); MS: 553.
    • EXAMPLE 19
  • This Example illustrates the preparation of N-[1-(3-phenyl-4-pentenyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (Compound No. 12 of Table III). [0181]
  • 5-Bromo-3-phenylpent-1-ene (131 mg, 0.58 mmol), 4-(N-(4-fluorophenyl-acetamido)-N-methyl)aminopiperidine (73 mg, 0.29 mmol), potassium carbonate (120 mg, 0.87 mmol) and tetrabutylammonium iodide (5 mg) were stirred in DMF (3 ml). After 16 h, water was added and the mixture extracted with EtOAc (2×20 ml). The organics were combined and washed with water, dried (MgSO[0182] 4), concentrated and purified by Bond Elut chromatography (eluent DCM, followed by 2.5% EtOW/DCM and finally 5% EtOH/DCM) to afford the title compound as an oil (55 mg, 0.14 mmol); MS: 395.
    • EXAMPLE 20
  • This Example illustrates the preparation of N-[1-(3-phenyl-3-azetidinylpropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide dihydrochloride (Compound No. 13 of Table III). [0183]
  • To a solution of N-[1-(3-phenyl-3-chloropropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (120 mg, 0.3 mmol) in DCM (5 mL) was added azetidine (0.12 mL, 1.8 mmol) and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was washed with water, dried (MgSO[0184] 4) concentrated, and purified by Bond Elut chromatography (eluent 5% MeOH/DCM followed by 10% MeOH/DCM) to afford the title compound as an oil which was then treated with ethereal HCl to provide N-[1-(3-phenyl-3-azetidinylpropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide dihydrochloride as a white solid (35 mg, 24%); NMR (d6-DMSO, 373K): 1.5-1.65 (m, 2H), 1.85-2.1 (m, 4H), 2.55-2.9 (m, 8H), 3.1-3.2 (m, 1H), 3.25-3.35 (m, 1H), 3.6-3.75 (m, 5H), 4.1-4.2 (m, 2H), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H), 7.35-7.5 (m, 5H); MS: 424.
    • EXAMPLE 21
  • This Example illustrates the preparation of N-[1-(3-phenyl-3-[4-fluorophenyl]propyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 15 of Table III). [0185]
  • To a solution of 4-(N-(4-fluorophenylacetamido)-N-methyl)aminopiperidine (143 mg, 1.74 mmol) in DMF (5 mL) was added 3-phenyl-3-(4-fluorophenyl)-1-bromopropane (Method V) (420 mg, 1.5 mmol) and K[0186] 2CO3 (300 mg). The reaction was then stirred overnight and poured onto water (20 mL). Extracted into EtOAc, washed with water (20 mL), brine (20 mL), and dried over MgSO4. The solvents were evaporated and the crude product was purified by Bond Elut chromatography (eluent 5% MeOH/DCM) to afford the title compound as a sticky gum, (148 mg, 20%); NMR: 1.65 (2H, m), 2.20 (1H, broad t), 3.2-2.6 (9H, m), 3.8-3.6 (6H, m), 4.10 (1H, m) and 7.4-7.2 (13H, m); MS: 463.
    • EXAMPLE 22
  • This Example illustrates the preparation of N-[1-(3,3-di-[4-fluorophenyl]propyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 16 of Table III). [0187]
  • To a DMF solution of 1-(3,3-di-(4-fluorophenyl)propyl)-4-(methylamino)piperidine (250 mg, 0.72 mmol, in 5 mL) was added 4-fluorophenylacetic acid (115 mg, 0.75 mmol), HATU (285 mg, 0.75 mmol), and DIPEA (130 μl). The reaction was stirred overnight and poured into water (20 mL). The organics were extracted into EtOAc (20 mL) and dried over MgSO[0188] 4. The desired product was then precipitated from the EtOAc by addition of 2M HCl in Et2O, to afford a pale yellow gum (139 mg, 46%); NMR: 1.60 (2H, m), 2.20 (2H, m), 2.75 (3H, s), 3.3-3.7 (12H, m), 6.80 (2H, m) and 7.3-7.0 (10H, m); MS: 481.
    • EXAMPLE 23
  • This Example illustrates the preparation of N-[1-(N,N-diphenyl-2-ethylamino)-4-piperidinyl]-N-allyl-4-methanesulfonylphenylacetamide (Compound No. 18 of Table III). [0189]
  • To a mixture of N-(4-piperidinyl)-N-allyl-4-methanesulfonylphenylacetamide (0.25 g, 0.74 mmol) and 4-methyl-2-pentanone (10 μL) was added potassium carbonate (0.31 g), potassium iodide (100 mg) and N-(2-bromoethyl)diphenylamine (0.21 g) and the resulting mixture was stirred and heated to reflux for 18 h. After cooling, water was added and the volatiles removed by evaporation. The residue was extracted three times with ethyl acetate and the combined extracts were dried and concentrated to give an oil which was purified by eluting through a silica gel column with 1% methanol in dichloromethane then 5% methanol in dichloromethane to give the title compound (73 mg); NMR: 1.5 (m, 4H), 2.1 (m, 2H), 2.5 (m, 2H), 3.1 (s, 3H), 3.8 (m, 7H), 3.9 (s, 2H), 5.1 (m, 2H), 5.8 (m, 1H), 6.9 (m, 6H), 7.2 (m, 4H), 7.4 (d, 2H), 7.8 (d, 2H); MS: 532. [0190]
    • EXAMPLE 24
  • This Example illustrates the preparation of N-[1-(N-phenyl-N-[2-(4-hydroxyphenyl)ethylcarbonyl]-2-ethylamino)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 20 of Table III). [0191]
  • To 3-(4-hydroxyphenyl)propanoic acid (0.1 mmol) was added DMF (5 μL) followed by oxalyl chloride (1 mL of a 0.1M solution in DCM, 0.1 mmol) and the resulting mixture was shaken at room temperature for 2 h. 100 μL Of this mixture was then added to 100 μL of a solution of N-[1-(N-phenyl-2-ethylamino)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (230 mg, 0. mmol) and triethylamine (0.334 mL, 2.4 mmol) in DCM (12 mL). The resulting mixture left at room temperature for 20 h then water (250 μL) and DCM (250 μL) were added and the mixture was shaken. The aqueous phase was removed and the organic phase was concentrated giving the title compound which was characterised by LC-MS; MS: 591. [0192]
    • EXAMPLE 25
  • This Example illustrates the preparation of N-[1-(3-phenyl-3-aminopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide dihydrochloride (Compound No. 23 of Table III). [0193]
  • To a solution of 3-phenyl-3-Bocaminopropanal (513 mg, 2.0 mmol) and N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (645 mg, 2.0 mmol) in methanol (15 mL) was added acetic acid (0.2 mL) and the resulting mixture was stirred at room temperature for 1 h. Sodium triacetoxyborohydride (844 mg, 4.0 mmol) was added and the mixture was stirred at room temperature for 18 h then evaporated. The residue was partitioned between DCM and water, and the organic phase was washed with brine, dried and concentrated. The residue was suspended in 4M HCl in dioxane (20 mL) and methanol (5 mL) was added. The resulting mixture was heated to reflux for 7 h, then cooled to room temperature and concentrated giving an oily residue which was purified by silica gel chromatography (eluent 5% MeOH/DCM then 10% MeOH/DCM) yielding the title compound as a solid (675 mg); NMR (d6 DMSO at 373K): 1.1 (t, 3H), 1.5 (m, 2H), 1.9 (m, 2H), 2.0 (m, 1H), 2.3 (m, 2H), 3.0 (m, 1H), 3.2 (m, 4H), 3.3 (q, 2H), 3.9 (s, 2H), 4.0 (m, 1H), 4.4 (m, 1H), 7.4 (m, 3H), 7.5 (m, 4H), 7.9 (m, 2H); MS: 458. [0194]
    • EXAMPLE 26
  • This Example illustrates the preparation of N-[1-(3-phenyl-3-benzoylaminopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 1 of Table IV). [0195]
  • A solution of benzoic acid (0.005 mmol) in NMP (50 μL) was added to a solution of HATU (0.01 mmol) and diisopropylethylamine (0.03 mmol) in NMP (100 μL). To the resulting mixture was added N-[1-(3-phenyl-3-aminopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide dihydrochloride (Example 25; 0.005 mmol) in NMP (100 μL). The mixture was left at room temperature for 18 h, then evaporated. The residue was partitioned between DCM (250 μL) and water (250 μL) and the phases separated. The organic phase was concentrated giving the title compound which was characterised by LC-MS; MS: 562. [0196]
    • EXAMPLE 27
  • This Example illustrates the preparation of N-[1-(N-Phenyl-2-ethylamino)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 24 of Table III). [0197]
  • To a mixture of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (2.0 g, 6.2 mmol) and N-(2-chloroethyl)aniline hydrochloride (1.2 g, 6.2 mmol) (J. Med. Chem. 1965, 173) in 4-methyl-2-pentanone (15 mL) was added potassium carbonate (2.56 g, 18.6 mmol) and potassium iodide (150 mg, 0.9 mmol) and the resulting mixture stirred at reflux for 20 h. After cooling to room temperature the solid was removed by filtration and the filtrate concentrated. The residue was purified by Bond Elut chromatography (eluent 5% MeOH/DCM) to afford, after trituration with diethyl ether, the title compound as a white solid (1.30 g, 50%); NMR (d6 DMSO, 373K): 1.1 (t, 3H), 1.4 (m, 2H), 1.8 (m, 2H), 2.1 (m, 2H), 2.5 (m, 2H), 3.1 (m, 5H), 3.3 (q, 2H), 3.8 (s, 2H), 5.0 (m, 1H), 6.6 (m, 3H), 7.1 (dd, 2H), 7.5 (d, 2H), 7.8 (d, 2H); MS: 444. [0198]
  • Compound No. 25 of Table III was prepared according to the method of Example 27 using N-(4-pipenrdinyl)-N-ethyl-4-fluorophenylacetamide. NMR: 1.0 and 1.5 (t, 3H), 1.3 (m, 1H) 1.5 (m, 1H), 1.7 (m, 2H), 2.0 (m, 2H), 2.4 (m, 2H), 2.9 (m, 2H), 3.1 (m, 2H), 3.2 (m, 2H), 3.6 and 3.7 (s, 2H), 4.1 (m, 1H), 5.2 (br s, 1H), 6.5 (m, 3H), 7.0 (dd, 2H), 7.1 (dd, 2H), 7.2 (m, 2H); MS: 384. [0199]
    • EXAMPLE 28
  • This Example illustrates the preparation of Compound No. 26 of Table III. [0200]
  • To a solution of N-[1-(3-phenyl]-3-oxopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide hydrochloride (5.00 g, 10.1 mmol) in methanol (150 mL) was added sodium borohydride (0.96 g, 25.4 mmol) portionwise. The resulting mixture was stirred at room temperature for 20 h. Water (10 mL) was added and the mixture was evaporated. The residue was purified by silica column chromatography (gradient elution from ethyl acetate to 50% ethyl acetate/MeOH) to give the title compound (3.92 g, 84%); NMR: (CDCl[0201] 3): 1.14 and 1.23 (t, 3H), 1.56 (m, 1H), 1.75 (m, 2H), 1.83 (m, 3H), 1.98 (m, 1H), 2.20 (m, 1H), 2.56 (m, 1H), 2.66 (m, 1H), 3.02 (s, 3H), 3.10 (m, 1H), 3.18 (m, 1H), 3.31 (q, 2H), 3.57 and 4.49 (m, 1H), 3.79 and 3.80 (s, 2H), 4.94 (m, 1H), 7.23 (m, 1H), 7.34 (m, 4H), 7.44 (d, 2H) and 7.90 (d, 2H); MS: 459.
    • EXAMPLE 29
  • This Example illustrates the preparation of N-[1-(4,4-diphenyl-but-2-yl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide hydrochloride (Compound No. 27 of Table III). [0202]
  • N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (323 mg, 1 mmol) was dissolved in DCM (10 mL). Acetic acid (1 ml) and 4,4-diphenyl-2-butanone (384 mg, 1.5 mmol) was added followed by sodium triacetoxyborohydride (516 mg, 2.1 mmol). The reaction mixture was stirred at room temperature for 7 days. Water (10 ml) was added and the layers separated. The organic phase was washed with brine, dried (MgSO[0203] 4) and evaporated to dryness. The residue was purified by Bond Elut chromatography (eluent 5% MeOH/DCM). The resultant oily residue was dissolved in a small amount of DCM, 1M HCl in diethyl ether was added and the mixture concentrated to yield the title compound as a white solid (120 mg, 22%); NMR (d6-DMSO, 373K): 1.0-1.2 (m, 6H), 1.5-2.1 (m, 6H), 2.5-3.0 (m, 6H), 3.1 (s, 3H), 3.3 (q, 2H), 3.8 (s, 2Hs), 4.1 (t, 1H) 7.1 (m, 2H), 7.2-7.4 (m, 8H), 7.5 (d, 2H), 7.9 (d, 2H); MS: 533.
    • EXAMPLE 30
  • This Example illustrates the preparation of N-[1-(4-phenyl-but-2-yl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 28 of Table III). [0204]
  • To a mixture of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (324 mg, 1 mmol), 4-phenyl-2-butanone (0.22 ml, 1.5 mmol), sodium triacetoxyborohydride (318 mg, 1.5 mmol) and acetic acid (0.11 ml, 2 mmol) in DCM (8 ml) was added a little MgSO[0205] 4 and the resulting mixture heated to reflux for 48 h. The reaction mixture was eluted through a column of silica gel (isohexane then 89% DCM/10% MeOH/10% NH4OH) yielding the title compound (60 mg); NMR (CDCl3): 1.1 and 1.2 (t, 3H), 1.3 (t, 3H), 1.6 (br m, 2H), 1.8 (m, 1H), 2.0 (s, 2H), 2.1 (m, 2H), 2.6 (br m, 3H), 3.0 (s, 3H), 3.2 (br m, 2H), 3.3 (q, 2H), 3.8 (s, 2H), 4.5 (m, 1H), 7.2 (m, 3H), 7.3 (m, 2H), 7.4 (m, 2H) and 7.9 (m, 2H); MS: 457.
    • EXAMPLE 31
  • This Example illustrates the preparation of N-[1-(3-[3-trifluoromethylphenyl]-butyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 29 of Table III). [0206]
  • To a solution of N-(4-pipetidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (680 mg, 2.1 mmol) in MeOH/DCM (10 ml, 1:1) was added 3-(3-trifluoromethylphenyl)butyraldehyde (Method BP) (500 mg, 2.3 mmol) and acetic acid (0.25 ml). The resulting mixture was stirred at room temperature for 30 min. then sodium triacetoxyborohydride (735 mg, 3.2 mmol) was added. The resulting mixture was stirred at room temperature for 2 h then quenched with water (5 ml) and concentrated to a third of the volume. The residual mixture was extracted with DCM and the organic extracts washed with saturated NaHCO[0207] 3 solution and brine and evaporated to give the title compound (260 mg); NMR (CDCl3): 1.18 (t, 3H), 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 6H), 2.0 (m, 2H), 2.2 (m, 2H), 2.8 (m, 3H), 3.05 (s, 3H), 3.3 (m, 2H), 3.8 (d, 2H), 7.4 (m, 6H), 7.9 (d, 2H); NMR: 525.
  • Compound No. 30 of Table III: NMR (CDCl[0208] 3): 1.18 (t, 3H), 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 8H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 2H), 3.05 (s, 3H), 3.3 (q, 2H), 3.8 (d, 2H), 7.05 (d, 1H), 7.2 (m, 3H), 7.45 (m, 2H), 7.9 (d, 2H); MS: 491.
  • Compound No. 31 of Table III: NMR (CDCl[0209] 3): 1.18 (t, 3H), 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 8H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9 (m, 2H), 3.05 (s, 3H), 3.3 (q, 2H), 3.8 (d, 2H), 7.2 (d, 3H), 7.3 (m, 2H), 7.45 (m, 2H), 7.9 (d, 2H); MS: 457.
  • Compound No. 32 of Table III: NMR (CDCl[0210] 3): 1.18 (t, 3H), 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 8H), 2.2 (m, 2H), 2.7 (m, 1H), 2.9(m, 2H), 3.05 (s, 3H), 3.3 (q, 2H), 3.8 (d, 2H), 7.0 (d, 1H) 7.35 (d, 1H), 7.45 (d, 2H), 7.9 (d, 2H); MS: 525.
    • EXAMPLE 32
  • This Example illustrates the preparation of N-[1-(3,3-diphenylpropyl)-3-pyrrolidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 33 of Table III). [0211]
  • To a solution of 4-methanesulfonylphenylacetic acid (1.01 g, 4.72 mmol) in DCM (20 ml) was added carbonyldiimidazole (765 mg, 4.72 mmol) and the resulting mixture stirred at room temperature for 2 h. A solution of 3-amino-1-(3,3-diphenylpropyl)pyrrolidine di-(trifluoroacetic acid) salt (Method BQ) (2.4 g, 4.72 mmol) and triethylamine (1.43 g, 11.4 mmol) in DCM (10 mL) was added and the resulting mixture stirred at room temperature for 2 h. The mixture was washed twice with water (50 ml), dried and evaporated. The residue was purified by silica column chromatography (eluent DCM then ethyl acetate) giving the title compound (1.6 g); NMR: 1.5 (m, 1H), 2-2.2 (m, 6H), 2.6 (m, 2H), 3.5 (s, 2H), 3.95 (t, 1H), 4.1(m, 2H), 7.1-7.3 (m 10H), 7.5(d, 2H), 7.8(d, 2H), 8.3 (d, 1H); MS: 477. [0212]
    • EXAMPLE 33
  • This Example illustrates the preparation of N-[1-(3-[4-chlorophenyl]-3-[4-pyridyl]propyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide (Compound No. 34 of Table III). [0213]
  • N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (480 mg, 1.47 mmol) was dissolved in DCM (40 ml). Acetic acid (6 ml) and 3-(4-chlorophenyl)-3-(4-pyridyl)propionaldehyde (Method BR) (2.2 mmol) was added and the mixture stirred at room temperature for 30 min. followed by the addition of sodium triacetoxyborohydride (340 mg, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was eluted through a column of silica gel (ethyl acetate then 89% DCM/10% MeOH/1% NH[0214] 4OH) yielding the title compound (60 mg); NMR (CDCl3): 1.1 and 1.3 (t, 3H), 1.5 (br m, 1H), 1.8 (m, 4H), 2.2 (m, 4H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (q, 2H), 3.5 (br m, 1H), 3.8 (m, 2H), 4.0 (m, 1H), 4.4 (br m, 1H), 7.1 (m, 4H), 7.3 (m, 2H), 7.5 (m, 2H), 7.9 (m, 2H) and 8.5 (m, 2H); MS: 554.
    Compound
    No in
    Table III 1H NMR (CDCl3)
    35 1.1 and 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (br m, 4H), 2.0 (m,
    1H), 2.2 (m, 3H), 2.4 (m, 1H), 2.9 (m, 2H), 3.0 (s, 3H),
    3.3 (q, 2H), 3.8 (m, 2H), 4.1 (m, 1H), 4.4 (m, 1H), 7.1
    (m, 2H), 7.2 (m, 4H), 7.4 (m, 2H), 7.6 (t, 1H), 7.9 (d, 2H)
    and 8.5 (m, 1H)
    36 1.1 and 1.2 (t, 3H), 1.5 (br m, 1H), 1.7 (b rm, 4H), 2.0
    (m, 1H), 2.2 (m, 2H), 2.3 (m, 2H), 2.4 (m, 1H), 2.9 (m,
    2H), 3.0 (s, 3H), 3.3 (q, 2H), 3.5 (m, 1H), 3.8 (m, 2H),
    3.9 (t, 1H), 4.4 (m, 1H), 5.9 (s, 2H), 6.7 (s, 2H), 7.2
    (m, 4H), 7.4 (m, 2H) and 7.9 (d, 2H)
    37 1.1 and 1.2 (t, 3H), 1.4 (m, 1H), 1.7 (m, 2H), 1.8 (m, 2H),
    2.0 (br t, 1H), 2.2 (m, 2H), 2.4 (d, 1H), 2.9 (m, 2H), 3.0
    (s, 3H), 3.3 (m, 2H), 3.5 (m, 1H), 3.8 (m, 2H), 3.9 (m,
    1H), 4.4 (m, 1H), 7.2 (m, 9H), 7.4 (m, 2H) and 7.9 (d, 2H)
    38 1.1 and 1.2 (t, 3H), 1.7 (br m, 4H), 2.0 (m, 1H), 2.2 (m,
    2H), 2.4 (m, 1H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (m, 2H),
    3.5 (m, 1H), 3.6 (m, 1H), 3.8 (m, 2H), 4.0 (m, 1H), 4.4
    (m, 1H), 7.3 (m, 10H) and 7.9 (d, 2H)
    39 1.1 and 1.2 (t, 3H), 1.4 (m, 1H), 1.7 (m, 2H), 1.8 (m, 2H),
    2.0 (br t, 1H), 2.2 (m, 3H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3
    (m, 2H), 3.5 (m, 1H), 3.6 and 4.5 (m, 1H), 3.8 (m, 5H), 3.9
    (t, 1H), 6.8 (d, 2H), 7.2 (m, 7H), 7.4 (m, 2H) and 7.9
    (d, 2H)
    40 1.1 and 1.2 (t, 3H), 1.5 (m, 1H), 1.7 (m, 2H), 1.8 (m, 2H),
    2.2 (m, 3H), 2.4 (m, 1H), 2.9 (m, 2H), 3.0 (s, 3H), 3.3 (m,
    2H), 3.5 (m, 1H), 3.8 (m, 2H), 4.0 (br t, 1H), 4.4 (m, 1H),
    7.2 (m, 9H), 7.4 (m, 2H) and 7.9 (d, 2H)
    41 1.1 and 1.2 (t, 3H), 1.5 (m, 1H), 1.7 (m, 2H), 1.8 (m, 2H),
    2.0 (br t, 1H), 2.2 (m, 3H), 2.3 (s, 3H), 2.9 (m, 2H), 3.0
    (s, 3H), 3.3 (m, 2H), 3.5 (m, 1H), 3.6 and 4.4 (m, 1H), 3.8
    (m, 2H), 3.9 (t, 1H), 7.1 (m, 5H), 7.2 (m, 4H), 7.4 (m, 2H)
    and 7.9 (d, 2H)
    42 1.1 and 1.3 (t, 3H), 1.5 (m, 1H), 1.7 (m, 4H), 2.0 (br t,
    1H), 2.2 (m, 3H), 2.4 (m, 1H), 2.9 (m, 2H), 3.0 (s, 3H),
    3.3 (m, 2H), 3.6 (br m, 2H), 3.8 (m, 2H), 4.0 (m, 1H), 4.4
    (m, 1H), 7.3 (m, 11H) and 7.9 (d, 2H)
    43 1.1 and 1.3 (t, 3H), 1.5 (m, 2H), 1.7 (m, 4H), 1.9 (m, 2H),
    2.2 (m, 2H), 2.9 (m, 1H), 3.0 (s, 3H), 3.1 (m, 1H), 3.4 (m,
    2H), 3.8 (m, 2H), 4.0 (t, 1H), 4.4 (m, 1H), 7.0 (m, 4H), 7.2
    (m, 4H), 7.4 (d, 2H) and 7.9 (d, 2H).
    44 1.6 (m, 4H), 2.0 (m, 2H), 2.2 (m, 4H), 2.9 (d, 2H), 3.0 (s,
    3H), 3.7 and 3.8 (s, 2H), 3.9 (m, 3H), 4.5 (m, 1H), 5.1 and
    5.3 (m, 2H), 5.8 (m, 1H), 6.9 (m, 4H), 7.1 (m, 4H), 7.4 (d,
    2H) and 7.9 (d, 2H).
  • Starting materials are commercially available, have been described in the literature or can be prepared by adaptation of literature methods. Examples of literature methods include: P. Richter, Ch. Garbe and G. Wagner, [0215] E. Ger. Pharmazie, 1974, 29(4), 256-262; C. Oniscu, D. Nicoara and G. Funieru, “4-(Ureidosulfonyl)phenylacetic acid and its ureide”, RO79-966646, (Romanian document); and M. A. Zahran, M. M. Ali, Y. A. Mohammed and A. A. Shehata, Int. J. Chem., 1993, 4(3), 61.
  • Method A [0216]
  • 4-Methylamino-1-N-(3,3-diphenylpropyl)piperidine dihydrochloride [0217]
  • To a solution of 4-tert-butoxycarbonylamino-1-N-(3,3-diphenylpropyl)piperidine (Method I) (15.9 g, 40 mmol) in THF (300 ml) was added lithium aluminium hydride (60 ml, 1M solution in THF, 60 mmol) and the mixture was refluxed. After 5 h the reaction mixture was cooled and sodium hydroxide was added carefully. The resultant granular precipitate was filtered off and the filtrate partitioned between water and EtOAc. The organic layer was dried (MgSO[0218] 4) and concentrated to a half of the original volume. 1M HCl in diethyl ether was then added to give the title compound as a white solid (13.8 g, 37 mmol); MS: 310.
  • Method B [0219]
  • 4-Methylamino-1-N-(3-R/S-phenylbutyl)piperidine dihydrochloride [0220]
  • To a solution of 4-tert-butoxycarbonylamino-1-N-(3-R/S-phenylbutyl)piperidine (Method J) (22 g, 66 mmol) in THF (500 μl) was added lithium aluminium hydride (100 ml, 1M solution in THF, 0.1 mol) and the mixture was refluxed. After 5 h the reaction mixture was cooled and 3M sodium hydroxide and water were added carefully. The resultant granular precipitate was filtered off and the filtrate partitioned between water and EtOAc. The organic layer was dried (MgSO[0221] 4) and concentrated to a half of the original volume. 1M HCl in diethyl ether was then added to give the title compound as a white solid (21 g, 66 mmol); NMR: 1.2 (d, 3H), 2.0 (m, 6H), 2.8 (m, 4H), 3.4 (m, 7H), 7.1 (m, 5H), 9.3 (br s, 1H); MS: 247.
  • Method C [0222]
  • 4-Propargylamino-1-N-(3-R/S-phenylbutyl)piperidine [0223]
  • To a solution of 1-(3-R/S-phenylbutyl)-4-piperidone (Method K) (500 mg, 2.2 mmol) in MeOH (8 ml) and acetic acid (2 ml) was added propargylamine (0.18 ml, 2.6 mmol). After 45 mins, sodium cyanoborohydride (170 mg, 2.7 mmol) was added and the reaction mixture left to stir at ambient temperature. After 16 h EtOAc was added and the reaction mixture was partitioned with dilute brine. The organic layer was separated, dried (MgSO[0224] 4) and concentrated to give the title compound as an oil (330 mg, 1.2 mmol); MS: 271.
  • Method D [0225]
  • 4-Allylamino-1-N-(3,3-diphenylpropyl)piperidine [0226]
  • To a solution of 1-(3,3-diphenylpropyl)-4-piperidone (Method L) (500 mg, 2.2 mmol) in MeOH (8 ml) and acetic acid (2 ml) was added allylamine (0.19 ml, 2.6 mmol). After 45 mins, sodium cyanoborohydride (135 mg, 2.2 mmol) was added and the reaction mixture left to stir at ambient temperature. After 16 h EtOAc was added and the reaction mixture was partitioned with dilute brine. The organic layer was separated, dried (MgSO[0227] 4) and concentrated to give the title compound as an oil (170 mg, 0.50 mmol); MS: 335.
  • Method E [0228]
  • 4-Allylamino-1-N-(3-R/S-phenylbutyl)piperidine [0229]
  • To a solution of 1-(3-R/S-phenylbutyl)-4-piperidone (Method K) (500 mg, 2.2 mmol) in MeOH (8 ml) and acetic acid (2 ml) was added allylamine (0.19 ml, 2.6 mmol). After 45 mins, sodium cyanoborohydride (170 mg, 2.7 mmol) was added and the reaction mixture left to stir at ambient temperature. After 16 h EtOAc was added and the reaction mixture was partitioned with dilute brine. The organic layer was separated, dried (MgSO[0230] 4) and concentrated to give the title compound as an oil (180 mg, 0.66 mmol); MS: 273.
  • Method F [0231]
  • 4-Piperidinyl-N-2-phenylethyl-2,4-difluorophenylurea.trifluoroacetic acid salt [0232]
  • To a solution of 1-tert-butyoxycarbonylpiperidin-4-yl-N-2-phenylethyl-2,4-difluorophenylurea (Method O) (300 mg, 0.65 mmol) in DCM (4 ml) was added trifluoroacetic acid (1 ml). After 2 h the reaction mixture was concentrated to give the title compound as an oil (0.31 g, 0.65 mmol); MS: 360. [0233]
  • Method G [0234]
  • 4-Amino-1-(3,3-diphenylpropyl)piperidine [0235]
  • To a solution of 4-tert-butoxycarbonylamino-1-N-(3,3-diphenylpropyl)piperidine (Method I) (10 g, 25 mmol) in DCM (100 ml) was added trifluoroacetic acid (20 ml) dropwise. After 3 h, toluene was added and the reaction mixture was concentrated to give the di-trifluoroacetic acid salt of the title compound as an oil (9.7 g, 19 mmol); MS: 295. [0236]
  • Method H [0237]
  • 4-Amino-1-(3-R/S-phenylbutyl)piperidine.ditrifluoroacetic acid salt [0238]
  • To a solution of 4-tert-butoxycarbonylamino-1-(3-R/S-phenylbutyl)piperidine (Method J) (13.1 g, 39.5 mmol) in DCM (150 ml) was added trifluoroacetic acid (30 ml) dropwise. After 15 h, toluene was added and the reaction mixture was concentrated to give the di-trifluoroacetic acid salt of the title compound as an oil (12.8 g, 27.8 mmol); MS: 233. [0239]
  • Method I [0240]
  • 4-tert-Butoxycarbonylamino-1-N-(3,3-diphenylpropyl)piperidine [0241]
  • To a solution of 4-(Boc-amino) piperidine (10 g, 50 mmol) in acetonitrile (200 ml) was added 3,3-diphenylpropyl bromide (15.1 g, 55 mmol), tetrabutylammonium iodide (2 g, 5 mmol) and potassium carbonate (15 g, 100 mmol) and the mixture refluxed. After 5 h the reaction mixture was cooled and poured into water. The solution was partitioned with EtOAc and the organic layer dried (MgSO[0242] 4), concentrated and purified by column chromatography (toluene:EtOAc, 1:1 with 1% triethylamine) to give the title compound as an oil (15.9 g, 40 mmol); MS: 395.
  • Method J [0243]
  • 4-tert-Butoxycarbonylamino-1-(3-R/S-phenylbutyl)piperidine [0244]
  • To a stirred solution of 4-(Boc-amino) piperidine (45 g, 0.225 mol) in methanol (160 ml) was added 3-R/S-phenylbutyraldehyde (36.5 ml, 0.25 mol) followed by acetic acid (115 ml). After 1 hour, sodium triacetoxyborohydride (71.5 g, 0.34 mol) was added portionwise over 30 mins [Caution: effervescence and exotherm]. After 15 h water (60 ml) was added and the total mixture was concentrated to remove the methanol. Water (250 ml) was added and the mixture was extracted with EtOAc (3×500 ml). The combined organics were washed with water, brine and dried (MgSO[0245] 4) to give the title compound as a white solid that was further recrystallised from DCM/EtOAc (54.1 g, 0.163 mol); m pt 220-221° C.; NMR: 1.2 (m, 3H), 1.4 (s, 9H), 1.7 (m, 2H), 2.0 (m, 6H), 2.8 (m, 4H), 3.3 (m, 2H), 7.0 (br s, 1H), 7.3 (m, 5H); MS: 333.
  • Method K [0246]
  • 1-(3-R/S-phenylbutyl)-4-piperidone [0247]
  • A solution of 1-(3-R/S-phenylbutyl)-4-piperidone ethylene ketal (Method M) (6.45 g, 23 mmol) in 6M hydrochloric acid (80 ml) was heated to reflux. After 3 h the reaction mixture was cooled and the pH was adjusted to pH 10 by the addition of 1M NaOH. The mixture was extracted with DCM (3×30 mL) and the combined organics were dried (MgSO[0248] 4), concentrated and purified by flash column chromatography (DCM to 5% MeOH/DCM) to give the title compound as an oil (2.3 g, 10 mmol); NMR (CDCl3): 1.2 (d, 3H), 1.6 (s, 1H), 1.8 (q, 2H), 2.2-2.5 (m, 5H), 2.7 (m, 3H), 2.8 (q, 1H) and 7.1-7.4 (m, 5H); MS: 232.
  • Method L [0249]
  • 1-(3,3-Diphenylpropyl)-4-piperidone [0250]
  • The procedure described in Method K was repeated using 1-(3,3-diphenylpropyl)-4-piperidone ethylene ketal (Method N) (5.3 g, 16 mmol) in place of 1-(3-R/S-phenylbutyl)-4-piperidone ethylene ketal to give the title compound as an oil (4.6 g, 16 mmol); NMR (CDCl[0251] 3): 2.3 (m, 2H), 2.4 (m, 6H), 2.7 (m, 4H), 4.05 (q, 1H) and 7.1-7.4 (m, 10H).
  • Method M [0252]
  • 1-(3-R/S-Phenylbutyl)-4-piperidone ethylene ketal [0253]
  • To a solution of 4-piperidone ethylene ketal (10 g, 70 mmol) in MeOH (100 ml) was added acetic acid (5 ml) and 3-R/S-phenylbutyraldehyde (11.4 ml, 77 mmol) and the reaction mixture left to stir at ambient temperature. After 1 h sodium triacetoxyborohydride (21 g, 99 mmol) was added portionwise. After a further 3 h water was added and the methanol was partially removed by evaporation; more water was added and the mixture extracted with EtOAc (×3). The combined organics were washed with water, brine, dried (MgSO[0254] 4) and concentrated to give the title compound as an oil (17.8 g, 65 mmol); MS: 276.
  • Method N [0255]
  • 1-(3,3-Diphenylpropyl)-4-piperidone ethylene ketal [0256]
  • To a solution of 4-piperidone ethylene ketal (5 g, 35 mmol) in acetonitrile (50 ml) was added potassium carbonate (9.6 g, 70 mmol) followed by 3,3-diphenylpropylbromide (9.6 g, 35 mmol) and tetrabutylammonium hydrogensulphate (1 g). After 16 h water was added and the acetonitrile was partially removed by evaporation; the mixture was then extracted with EtOAc (×3). The combined organics were washed with water, brine, dried (MgSO[0257] 4), concentrated and purified by flash column chromatography (DCM to 8% MeOH/DCM) to give the title compound as an oil (5.3 g, 16 mmol); MS: 338.
  • Method O [0258]
  • 1-tert-Butyoxyarbonylpiperidin-4-yl-N-2-phenylethyl-2,4-difluorophenylurea [0259]
  • To a solution of 4-(2-phenylethylamino)-1-tert-butoxycarbonylpiperidine (Method P) (0.61 g, 2 mmol) in DCM (30 ml) was added 2,4-difluorophenylisocyanate (0.21 ml, 2 mmol). After 3 h water was added and the reaction mixture stirred for 20 mins. The organic layer was then separated and the aqueous layer partitioned with DCM. The combined organic layers were washed with water, dried (MgSO[0260] 4), concentrated and columned (20% EtOAc/iso-hexane to 40% EtOAc/iso-hexane) to give the title compound as an oil (0.73 g, 1.6 mmol); MS:460.
  • Method P [0261]
  • 4-(2-Phenylethylamino)-1-tert-butoxycarbonylpiperidine [0262]
  • To a solution of 1-tert-butoxycarbonylpiperid-4-one (10 g, 50 mmol) and 2-phemethylamine.hydrochloride (7.9 g, 50 mmol) in MeOH (250 ml) was added sodium cyanoborohydride (6.3 g, 100 mmol). After 1.5 h, water was added carefully and the MeOH was partially removed by evaporation. The mixture was extracted with DCM (×3); the organics were combined and washed with water, dried (MgSO[0263] 4), concentrated and purified by column chromatography (DCM to 5% MeOH/DCM) to give the title compound as an oil (13.4 g, 44 mmol); NMR (CDCl3): 1.5 (m, 9H), 1.9 (d, 2H), 2.2 (t, 4H), 2.8 (t, 2H), 2.9 (m, 2H), 3.0 (m, 2H), 3.85 (m, 1H), 4.1 (m, 2H) and 7.2-7.4 (m, 5H).
  • Method R [0264]
  • 4-(Cyclopropylmethyl)amino-1-(3-R/S-phenylbutyl)piperidine [0265]
  • To a solution of 1-(3-R/S-phenylbutyl)-4-piperidone (Method K) (500 mg, 2.2 mmol) in MeOH (8 ml) and acetic acid (2 ml) was added cyclopropyhmethylamine (0.2 ml, 2.6 mmol). After 45 mins, sodium cyanoborohydride (170 mg, 2.7 mmol) was added and the reaction mixture left to stir at ambient temperature. After 16 h EtOAc was added and the reaction mixture was partitioned with dilute brine. The organic layer was separated, dried (MgSO[0266] 4) and concentrated to give the title compound as an oil (230 mg, 1.2 mmol); MS: 287.
  • Method S [0267]
  • 4-Fluorocinnamanic acid tert-butyl ester [0268]
  • To a suspension of 4-fluorocinnamanic acid (1.66 g, 10 mmol) in toluene (15 mL) heated to 80° C., was added dimethylformamide di-tert-butylacetal (8.2 g, 40 mmol) dropwise, and the reaction heated for a further 30 minutes. Upon cooling, the reaction was partitioned between toluene and water (15 mL), and washed with NaHCO[0269] 3 solution (2×10 mL), and brine (10 mL). The organic layer was dried, and concentrated. Purified on a Bond Elut column (eluent DCM) to afford the desired product as a colourless oil (1.25 g, 5.6 mmol); NMR (CDCl3): 1.57 (9H, s), 6.28 (1 h, d), 7.07 (2H, t) and 7.50 (3H, m).
  • Method T [0270]
  • 3-Phenyl-3-(4-fluorophenyl)propionic acid tert-butyl ester [0271]
  • To a −78° C. solution of 4-fluorocinnamanic acid tert-butyl ester (Method S) (0.9 g, 4 mmol) in THF was added dropwise a solution of phenyllithium in hexanes (4 mL of 1.5M solution, 6 mmol). The reaction was stirred for 1 h and then quenched with water and extracted into EtOAc, dried and purified by Bond Elut chromatography (50:50 DCM/iso-hexane) to afford the title compound, as a colourless oil (500 mg, 1.8 mmol); NMR (CDCl[0272] 3): 1.21 (9H, s), 2.87 (2H, d), 4.40 (1H, t), 6.90 (2H, t) and 7.15 (7H, m).
  • Method U [0273]
  • 3-Phenyl-3-(4-fluorophenyl)-propan-1-ol [0274]
  • To a THF (10 mL) solution of 3-phenyl-3-(4-fluorophenyl)-propionic acid, tert-butyl ester (Method T) (495 mg, 1.65 mmol) was added LiAlH[0275] 4 in THF (2.5 ml of a 1.0M solution) and the reaction stirred at RT for 2 h. The reaction mixture was quenched cautiously with 2M aqueous NaOH, and the precipitate removed. The solution was then extracted with EtOAc, washed with water (20 mL) dried, MgSO4, and evaporated to afford the title compound as a pale solid, (379 mg, 1.65 mmol); NMR (CDCl3): 2.23 (2H, m), 3.65 (2H, t), 4.06 (1H, t), 6.90 (2H, m) and 7.20 (7H, m).
  • Method V [0276]
  • 3-Phenyl-3-(4-fluorophenyl)-1-bromopropane [0277]
  • To a solution of 3-phenyl-3-(4-fluorophenyl)-propan-1-ol (Method U) (379 mg, 1.65 mmol) in DCM (5 mL), was added carbon tetrabromide (564 mg, 1.7 mmol), and triphenyl phosphine (445 mg, 1.7 mmol). The reaction was stirred overnight, and filtered through a pad of silica, then evaporated. The title product was obtained as a pale white solid by Bond Elut chromatography, eluent iso-hexane, (415 mg, 86%); NMR (CDCl[0278] 3): 2.43 (2H, m), 3.20 (2H, t), 4.16 (1H, t), 6.90 (2H, m) and 7.20 (7H, m).
  • Method W [0279]
  • 4,4-Di-(4-fluorophenyl)-1-iodobutane [0280]
  • To a suspension of sodium iodide (1.5 g, 10 mmol) in acetone (100 mL) was added 4,4-di(4-fluorophenyl)-1-chlorobutane (2 g, 7 mmol), and refluxed for 5 h. The acetone was evaporated and the product was partitioned between water and EtOAc. The organic phase was dried (MgSO[0281] 4) and evaporated to give the title compound as a pale yellow oil, (3 g, 2:1 mixture of product to starting material); NMR (CDCl3): 1.80 (2H, m), 2.20 (2H, m), 3.20 (1 ⅓H, t, CH 2I), 3.55 (⅔H, t, CH 2Cl), 3.90 (1H, t), 6.96 (4H, m) and 7.16 (4H, m).
  • Method X [0282]
  • 4,4-Di-(4-fluorophenyl)-but-1-ene [0283]
  • The crude 4,4-di-(4-fluorophenyl)iodobutane (Method W) (3 g) was added to potassium tert-butoxide (1.3 g, 12 mmol) in THF (30 mL), and stirred overnight. The product was extracted into EtOAc and washed with water (100 mL). The organic phase was dried (MgSO[0284] 4) and evaporated to afford a yellow oil. This was purified by chromatography (silica, iso-hexane) to afford the desired product as a colourless oil. (1.4 g, 82%); NMR: 2.80 (2H, t), 4.00 (1H, t), 4.98 (1H, dd) 5.05 (1H, dd), 5.70 (1H, ddt), 7.00 (4H, m) and 7.20 (4H, m).
  • Method Y [0285]
  • 3,3-Di-(4-fluorophenyl)propanal [0286]
  • A DCM solution of 4,4-di-(4-fluorophenyl)-but-1-ene (Method X) (1.4 g, 5.7 mmol, in 20 mL) was cooled to −78° C. and exposed to ozone until a pale blue colour persisted (about 20 min). The reaction was then purged with oxygen until the colour faded, and finally quenched with triphenylphosphine (1.49 g, 5.7 mmol). Upon warning to RT the reaction was washed with water, dried (MgSO[0287] 4) and concentrated. The residue was passed through a plug of silica to afford the title product as a colourless oil, (1.18 g, 100%); NMR (CDCl3): 3.15 (2H, d), 4.60 (1H, t), 7.00 (4H, m), 7.18 (4H, m), 9.75 (1H, s).
  • Method Z [0288]
  • 1-(3,3-Di-[4-fluorophenyl]propyl)-4-([tert-butoxycarbonyl]amino)piperidine [0289]
    Figure US20040006081A1-20040108-C00010
  • To a solution of 3,3-di-(4-fluorophenyl)propanal (Method Y) (1.18 g, 5.7 mmol), in dichloroethane (14 mL) and 4-Bocaminopiperidine (1.2 g, 6 mmol) was added acetic acid (0.3 mL), 3 Å molecular sieves (2 g), and sodium triacetoxyborohydride (1.27 g, 6 mmol), and the reaction mixture stirred for 5 h. The mixture was poured onto water and extracted into EtOAc (30 mL), dried and evaporated. The title product was obtained by purification by chromatography (silica, 5% MeOH/DCM) to give the product as a solid (1.7 g, 69%); MS: 431. [0290]
  • Method AA [0291]
    Figure US20040006081A1-20040108-C00011
  • 1-(3,3-Di-[[0292] 4-fluorophenyl]propyl)-4-(methylamino)piperidine
  • To a solution of 1-(3,3-Di-[4-fluorophenyl]propyl)-4-([tert-butoxycarbonyl]amino)piperidine (Method Z) (1.7 g, 3.9 mmol) in THF (50 mL), was added LiAlH[0293] 4 solution (5 mL of a 1.0M solution in THF) dropwise (CARE gas evolution) and then the reaction was refluxed for 16 h. The reaction mixture was then cooled to RT and cautiously quenched with 2M NaOH, filtered to remove precipitate and partitioned between water and EtOAc. The organic layer was dried over MgSO4 and evaporated. The crude product was purified by chromatography (silica, eluent 1:1, toluene:EtOAc with 0.5% isopropylamine) to afford the title compound as a yellow oil (500 mg, 37%); NMR: 2.2-1.0 (9H, m), 2.67 (1H, m), 3.4-3.2 (4H, m), 3.90-4.10 (2H, m), 4.35 (2H, m), 7.05 (4H, m) and 7.30 (4H, m); MS: 345.
  • Method AB [0294]
  • 4-Ethylamino-1-N-(3,3-diphenylpropyl)piperidine [0295]
    Figure US20040006081A1-20040108-C00012
  • To a solution of 1-(3,3-diphenylpropyl)-4-piperidone (Method L) (2.2 g, 7.5 mmol) in DCM (30 ml) was added ethylamine (8.5 ml, 2M in THF, 17 mmol), sodium triacetoxyborohydride (1.6 g, 7.5 mmol) and 4 Å Molecular Sieves (10 rods). The reaction mixture left to stir at ambient temperature. After 16 h the mixture was filtered, washed with water, dried (NaSO[0296] 4) and concentrated to give the title compound as an oil (1.4 g, 4.35 mmol);
  • MS: 323. [0297]
  • Method AC [0298]
  • N[1-Phenylmethyl-piperidin-4-yl]-N-methyl-(4-fluorophenyl)acetamide [0299]
    Figure US20040006081A1-20040108-C00013
  • To a solution of 4-methylamino-1-N-(phenylmethyl)piperidine (2.95 g, 14.5 mmol) in DMF (25 ml) was added DIPEA (10 ml), 4-fluorophenylacetic acid (2.67 g, 17.3 mmol) and HATU (6.0 g, 16 mmol). After 16 h at RT water was added and the mixture was partitioned with EtOAc (×3). The organics were combined, washed with water and brine, dried (MgSO[0300] 4) and concentrated to give the title compound as a brown oil (4.90 g, 14.4 mmol); MS: 341. † 4-Methylamino-1-N-(phenylmethyl)piperidine is described in J. Med. Chem. 1999, 42, 4981-5001.
  • Method AD [0301]
  • 4-(N-(4-Fluorophenylacetamido)-N-methyl)aminopiperidine [0302]
    Figure US20040006081A1-20040108-C00014
  • To a solution of N-[1-phenylmethyl-piperidin-4-yl]-N-methyl-(4-fluorophenyl)acetamide(Method AC) (4.90 g, 14.4 mmol) in EtOH (50 ml) was added 20% palladium hydroxide on carbon (1 g) followed by ammonium formate (5.18 g, 82 mmol). The reaction mixture was then refluxed until the evolution of gas ceased at which point it was filtered through Celite® and concentrated to give the title compound as an oil (2.86 g, 11.4 mmol); MS: 251. [0303]
  • Method AE [0304]
  • 3-Phenylpent-4-enoic acid [0305]
  • Cinnamyl alcohol (5 g, 37 mmol), triethylorthoacetate (47 ml) and propionic acid (0.17 ml) were heated at 140° C. under a distillation head and condenser. After 1 h the reaction mixture was cooled and concentrated to give a pale yellow oil. This oil was dissolved in EtOH (15 ml) and water (15 ml) and NaOH (3.73 g, 93 mmol) was added and the mixture stirred at 80° C. After 16 h the mixture was heated to 100° C. for 2 h then allowed to cool. The reaction mixture was diluted with water (120 ml) and extracted with diethyl ether (2×150 ml). The aqueous layer was acidified with AcOH and then re-extracted with diethyl ether (3×150 ml). The organics were combined and dried (MgSO[0306] 4) and concentrated to give the desired product as a brown oil (5.52 g, 31 mmol); NMR: 2.65 (m, 2H), 3.75 (1, 1H), 4.95 (s, 1H), 5.05 (d, 1H), 5.95 (m, 1H), 7.2 (m, 5H), 12.1 (br s, 1H); MS: 177.
  • Method AF [0307]
  • 3-Phenylpent-4-en-1-ol [0308]
  • To a solution of 3-phenylpent-4-enoic acid (Method AE) (2.0 g, 11.4 mmol) in THF (20 ml) at 0° C. was added lithium aluminium hydride (12.5 ml, 1M solution in THF) dropwise over 15 mins and the reaction mixture was allowed to warm to RT. After 64 h water (2.4 ml) was added followed by 2N NaOH (2.4 ml) then water (7.2 ml). The resulting gelatinous precipitate was filtered, washed with THF and concentrated. The residue was dissolved in DCM and washed with saturated sodium hydrogen carbonate (2×150 ml), dried (MgSO[0309] 4) and concentrated to give the title compound as a pale yellow oil (1.8 g, 1.1 mmol); NMR: 1.8 (m, 2H), 3.4 (m, 2H), 4.4 (t, 1H), 5.0 (m, 2H), 5.9 (m, 1H) and 7.2 (m, 5H).
  • Method AG [0310]
  • 5-Bromo-3-phenylpent-1-ene [0311]
  • The procedure described in Method V was repeated except using 3-phenylpent-4-en-1-ol (1.75 g, 10.8 mmol), triphenylphosphine (3.12 g, 11.9 mmol), carbon tetrabromide (3.94 g, 11.9 mmol) and DCM (35 ml) to give the title compound as a colourless oil (2.02 g, 9 mmol); NMR: 2.2 (m, 2H), 3.4 (m, 3H), 5.1 (m, 2H), 5.95 (m, 1H) and 7.2 (m, 5H). [0312]
  • Method AH [0313]
  • N-[-(3-[4-Fluorophenyl]-3-oxopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide hydrochloride [0314]
    Figure US20040006081A1-20040108-C00015
  • To a solution of N-4-piperidinyl-N-ethyl-4-methanesulfonylphenylacetamide (1.3 g, 4.0 mmol) in DMF (25 mL) was added DIPEA (2 mL, 11.5 mmol) and 3-chloro-4′-fluoropropiophenone (770 mg, 4.0 mmol). The resulting mixture was stirred at room temperature overnight then evaporated. The residue was heated to reflux with 5% methanol in ethyl acetate giving a white solid which was isolated (1.6 g, 80%). NMR: 1.00 and 1.16 (t, 3H), 1.75 (t, 2H), 2.23 (q, 2H), 3.10 (t, 2H), 3.18 (s, 3H), 3.30 (m, 2H), 3.35 and 3.64 (q, 2H), 3.56 (m, 2H), 3.82 and 3.93 (s, 2H), 4.15 and 4.28 (m, 1H), 7.40 (m, 2H), 7.50 (m, 2H),7.83 (m, 2H), 8.07 (m, 2H); MS: 475. [0315]
  • Method AI [0316]
  • N-(4-Piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide [0317]
    Figure US20040006081A1-20040108-C00016
  • To a solution of N-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (34 g, 82 mmol) in ethanol (600 mL) was added ammonium formate (40 g). The mixture was purged with argon and 30% Pd on carbon (4.2 g) was added. The resulting mixture was stirred at reflux for 4 h, then allowed to cool and filtered through diatomaceous earth. The filtrate was evaporated to give a thick oil which solidified on standing to yield the title compound (24.9 g, 94%); NMR: 1.02 and 1.15 (t, 3H), 1.4-1.6 (br m, 4H), 2.45 (m, 2H), 2.93 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.32 (q, 2H), 3.72 and 4.18 (m, 1H), 3.80 and 3.87 (s, 2H), 7.50 (m, 2H), 7.85 (m, 2H); MS: 325 (MH+). [0318]
  • Method AJ [0319]
  • N-(1-Phenylmethyl-4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide [0320]
    Figure US20040006081A1-20040108-C00017
  • To a solution of 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride (32.0 g, 110 mmol) in DCM (500 mL) was added N,N-diisopropylethylamine (60 mL) with stirring to ensure complete dissolution. 4-Methanesulfonylphenylacetic acid (25.0 g, 117 mmol), 4-Dimethylaminopyridine (4-DMAP) (2.0 g) and dicyclohexylcarbodiimide (DCCI) (25.0 g, 121 mmol) were added and the resulting mixture was stirred at room temperature for 20 h. The precipitate was removed by filtration and the resulting solution was washed successively with 2N aqueous HCl, water and 1N aqueous NaOH, dried (MgSO[0321] 4) and evaporated. The residue was purified by silica gel chromatography (eluent 10% MeOH/ethyl acetate) to afford the title compound (35 g, 76%); NMR: 1.00 and 1.14 (t, 3H), 1.45 and 1.70 (m, 2H), 1.95 (br m, 2H), 2.80 (br m, 2H), 3.18 (s, 3H), 3.20 and 3.33 (q, 2H), 3.45 (s, 2H), 3.80 and 3.87 (s, 2H), 3.70 and 4.10 (m, 1H), 7.2-7.3 (m, 5H), 7.48 (m, 2H), 7.82 (m, 2H); MS: 415 (MH+).
  • Method AK [0322]
  • 1-Phenylmethyl-4-ethylaminopiperidine dihydrochloride [0323]
    Figure US20040006081A1-20040108-C00018
  • To a solution of 1-phenylmethyl-4-piperidone (25.0 g, 132 mmol) in THF (250 mL) was added ethylamine hydrochloride (12.0 g, 147 mmol) and methanol (50 mL) and the resulting mixture stirred at room temperature for 10 min. Sodium triacetoxyborohydride (40 g, 189 mmol) was added portionwise and the resulting mixture stirred at room temperature for 1 h. 2M Sodium hydroxide solution (250 mL) was added and the resulting mixture extracted with diethyl ether. The organic extracts were dried (K[0324] 2CO3) and evaporated to give 1-phenylmethyl-4-ethylaminopiperidine as an oil. This was dissolved in ethanol (500 mL) and concentrated hydrochloric acid (20 mL) was added. The resulting crystals were collected, washed with diethyl ether and dried giving the title compound as a solid (38 g); NMR: (CDCl3): 1.10 (t, 3H), 1.40 (m, 2H), 1.83 (m, 2H), 2.02 (m, 2H), 2.65 (q, 2H), 2.85 (m, 2H), 3.50 (s, 2H), 3.75 (m, 1H), 7.2-7.4 (m, 5H); MS: 219 (MH+).
  • Method AL [0325]
  • N-[1-(3-Phenyl-3-chloropropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide [0326]
    Figure US20040006081A1-20040108-C00019
  • To a cooled (5° C.) solution of N-[1-(3-phenyl-3-hydroxypropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (112 mg, 0.29 mmol) in DCM (5 mL) was added N,N-diisopropylethylanine (0.10 mL, 0.58 mmol) then methanesulfonyl chloride (0.03 mL, 0.35 mmol). The resulting mixture was stirred at ambient temperature for 18 h, then was concentrated. The residue was purified by Bond Elut chromatography (eluent DCM, followed by 5% MeOH/DCM) to afford the title compound as an oil (120 mg) which was characterised by LC-MS; MS: 403, 405. [0327]
  • Method AM [0328]
  • N-[1-(3-Phenyl-3-hydroxypropyl)piperidinyl]-N-methyl-4-fluorophenylacetamide [0329]
    Figure US20040006081A1-20040108-C00020
  • To a solution of N-[1-(3-phenyl-3-oxopropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide (300 mg, 0.78 mmol) in methanol (30 mL) was added sodium borohydride (120 mg) and the resulting mixture was stirred at room temperature for 2 h. Water (5 mL) was added and the mixture was concentrated. The residue was extracted with DCM and the organic extract was washed with water and brine, dried and concentrated to give the title compound (230 mg, 76%); NMR: 1.4 (m, 2H), 1.7 (m, 4H), 1.9 (m, 2H), 2.7 and 2.8 (s, 3H), 2.9 (m, 2H), 3.65 and 3.75 (s, 2H), 4.2 (m, 1H), 4.6 (m, 1H), 5.4 (br s, 1H), 7.1 (m, 2H), 7.2 (m, 3H), 7.3 (m, 4H); MS: 385. [0330]
  • Method AN [0331]
  • N-[1-(3-Phenyl-3-oxopropyl)-4-piperidinyl]-N-methyl-4-fluorophenylacetamide [0332]
    Figure US20040006081A1-20040108-C00021
  • To a solution of N-(4-piperidinyl)-N-methyl-4-fluorophenylacetamide (250 mg, 1.0 mmol) in DMF (10 mL) was added 3-chloropropiophenone (168 mg, 1.0 mmol) and DIPEA (0.35 mL, 2.0 mmol). The resulting mixture was stirred at room temperature for 3 h. Water and DCM were added and the phases separated. The organic phase was washed with brine, dried and concentrated. The residue was purified by silica column chromatography (eluent 10% MeOH in DCM) yielding the title compound (305 mg); NMR: 1.3 (m, 2H), 1.6 (m, 2H), 2.0 (m, 2H), 2.6 (s, 3H), 2.7 (m, 2H), 2.9 (m, 2H), 3.1 (t, 2H), 3.7 (m, 2H), 4.2 (m, 1H), 7.1 (m, 2H), 7.2 (m, 2H), 7.4 (dd, 2H), 7.6 (t, 1H), 7.9 (d, 2H); MS: 383. [0333]
  • Method AO [0334]
  • N-(2-Bromoethyl)diphenylamine [0335]
  • To a cooled (5° C.) solution of N,N-diphenylbromoacetamide (1.4 g, 5.0 mmol) in THF (20 mL) was added borane methyl sulfide complex (26 mL, 1.0M) gradually. The reaction mixture was stirred at room temperature for 4 h. 10% Acetic acid in methanol (30 mL) was added and the resulting mixture was stirred for 20 h. The solvent was removed by evaporation and the residue was partitioned between ethyl acetate and water. The organic phase was dried and concentrated to give the title compound (1.0 g); NMR (CDCl3): 3.52 (t, 2H), 4.10 (t, 2H), 7.00 (m, 4H), 7.23 (m, 6H). [0336]
  • Method AP [0337]
  • N,N-Diphenylbromoacetamide [0338]
  • To a cooled (5° C.) solution of diphenylamine (2.0 g, 12 mmol) in DMF (15 mL) was added sodium hydride (520 mg, 60% dispersion) followed by bromoacetyl bromide (3.58 g) and the resulting mixture was stirred for 2 h. Water was added gradually, then the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed three times with brine, dried (MgSO[0339] 4) and evaporated to yield the title compound (3.4 g, 99%); NMR (CDCl3): 3.83 (S, 2H), 7.35 (m, 10H).
  • Method AQ [0340]
  • N-(4-Piperidinyl)-N-allyl-4-methanesulfonylphenylacetamide [0341]
    Figure US20040006081A1-20040108-C00022
  • To a solution of N-(1-phenylmethyl-4-piperidinyl)-N-allyl-4-methanesulfonylphenylacetamide (4.40 g, 10.3 mmol) in DCM (30 mL) under an argon atmosphere and the mixture cooled in an ice-water bath. 1-Chloroethyl chloroformate (1.34 mL, 12.4 mmol) was added and the resulting mixture was stirred for 3 h while warming to room temperature. The mixture was evaporated and the residue dissolved in methanol (30 mL). The resulting mixture was refluxed for 1 h, allowed to cool and concentrated. The crude product was purified by silica column chromatography (eluent 5% EtOH/DCM then 15% EtOH/2% isopropylamine/DCM) to give the title compound (1.30 g); NMR: 1.50 (m, 4H), 2.50 (m, 2H), 2.95 (m, 2H), 3.20 (s, 3H), 3.74 and 3.91 (s, 1H), 3.80 and 3.95 (d, 1H), 4.29 (m, 1H), 5.00 and 5.05 (d, 1H), 5.20 (m, 1H), 5.73 and 5.89 (dddd, 1H), 7.44 and 7.49 (d, 2H), 7.85 (m, 2H). [0342]
  • Method AR [0343]
  • N-(1-Phenylmethyl-4-piperidinyl)-N-allyl-4-methanesulfonylphenylacetamide [0344]
    Figure US20040006081A1-20040108-C00023
  • This was prepared by reacting 1-phenylmethyl-4-allylamine with 4-methanesulfonylphenylacetamide according to the procedure used for Method AJ; NMR (d6-DMSO, 373K): 1.65 (m, 2H), 1.88 (m, 2H), 2.39 (m, 2H), 3.05 (m, 2H), 3.09 (s, 3H), 3.75 (m, 4H), 3.93 (s, 2H), 4.08 (m, 1H), 5.15 (m, 2H), 5.82 (dddd, 1H), 7.30 (m, 5H), 7.45 (d, 2H), 7.80 (d, 2H). [0345]
  • Method AS [0346]
  • 1-Phenylmethyl-4-allylamine [0347]
  • This was prepared by reacting 1-phenylmethyl-4-piperidone with allylamine according to the procedure used for Method AK; NMR (CDCl[0348] 3): 1.4 (m, 2H), 1.5 (m, 2H), 1.9 (m, 2H), 2.0 (dd, 2H), 2.5 (m, 1H), 2.8 (m, 2H), 3.3 (d, 2H), 3.5 (s, 3H), 5.1 (d, 1H), 5.2 (d, 1H), 5.9 (dddd, 1H), 7.3 (m, 5H); MS: 231 (MH+).
  • Method AT [0349]
  • N-4-Piperidinyl-N-ethyl-4-fluorophenylacetamide [0350]
    Figure US20040006081A1-20040108-C00024
  • This was prepared by reacting N-(1-phenylmethyl-4-piperidinyl)-N-ethyl-4-fluorophenylacetamide according to the procedure used for Method AI; NMR: (formic acid salt): 0.97 and 1.10 (t, 3H), 1.46 and 1.62 (m, 2H), 1.8-2.0 (m, 2H), 2.78 (m, 2H), 3.1-3.3 (m, 4H), 3.65 and 3.74 (s, 2H), 3.97 and 4.22 (m, 1H), 7.08 (m, 2H), 7.25 (m, 2H), 8.42 (s, 1H); MS: 265. [0351]
  • Method AU [0352]
  • 3-Phenyl -3-Boc-aminopropanal [0353]
    Figure US20040006081A1-20040108-C00025
  • A solution of 3-phenyl-2-Boc-aminopropanol (700 mg, 2.78 mmol) in DCM (8 mL) was added to a stirred solution of Dess-Martin periodinane (1.30 g, 3.06 mmol) in DCM (5 mL) at room temperature followed by pyridine (0.3 mL). After stirring for 6 h at room temperature the mixture was partitioned between diethyl ether and saturated aqueous sodium bicarbonate solution containing sodium thiosulfate. The organic phase was washed with water and brine, dried and concentrated giving the title compound as a solid (790 mg); NMR: 1.4 (s, 9H), 2.8 (m, 2H),.5.1 (m, 1H), 7.3 (m, 5H), 8.6 (m, 1H), 9.6 (t, 1H). [0354]
  • Method AV [0355]
  • 3-Phenyl-2-Boc-aminopropanol [0356]
    Figure US20040006081A1-20040108-C00026
  • To a solution of 3-phenyl-3-Bocaminopropanoic acid (1.0 g, 3.78 mmol) in THF (10 mL) was added borane-THF complex (7.5 mL, 1.5M, 11.3 mmol) at 0° C. The resulting mixture was stirred with warming to room temperature for 5 h. 10% Acetic acid in methanol (20 mL) was added dropwise, the resulting mixture was concentrated and the residue partitioned between DCM and 1M aqueous HCl. The organic phase was washed with water and brine, dried (MgSO[0357] 4) and concentrated. The residue was purified by Bond Elut chromatography (eluent 5% MeOH/DCM) to afford the title compound (900 mg).
  • Method AW [0358]
  • 3-Phenyl-3-Boc-aminopropanoic acid [0359]
    Figure US20040006081A1-20040108-C00027
  • To a solution of DL-3-amino-3-phenylpropanoic acid (5 g, 30.2 mmol) in 2M aqueous sodium hydroxide (70 mL) was added a solution of di-tert-butyldicarbonate (8.56 g, 39.2 mmol) in THF (60 mL) and the resulting mixture stirred at room temperature for 48 h. Water (50 mL) was added and the mixture washed twice with ethyl acetate (50 mL). The aqueous phase was acidified to pH 3 with concentrated aqueous HCl, and the resulting mixture was extracted twice with ethyl acetate (60 mL). The combined organic extracts were dried (MgSO[0360] 4) and concentrated to give the title compound as a white solid (4.8 g); NMR: 1.4 (s, 9H), 2.7 (m, 2H), 4.8 (m, 1H), 7.3 (m, 5H), 7.5 (br d, 1H), 12.1 (br s, 1H); MS: 266.
  • Method AX [0361]
  • 4-Cyclopropylamino-1-(3,3-diphenylpropyl)piperidine [0362]
  • This was prepared using a method similar to that used for 4-ethylamino-1-(3,3-diphenylpropyl)piperidine (Method AB). NMR: 0.0 (m, 2H), 0.2 (m, 2H); 1.1 (m, 2H), 1.55 (m, 2H), 1.7 (m, 2H), 1.9 (m, 5H), 2.5 (m, 2H), 3.7 (m, 1H), 6.9 (m, 2H), 7.1 (m, 8H); MS: 335. [0363]
  • Method AY [0364]
  • 4-(2-Hydroxyethylamino)-1-(3,3-diphenylpropyl)piperidine [0365]
  • This was prepared using a method similar to that used for 4-ethylamino-1-(3,3-diphenylpropyl)piperidine. NMR: 1.2 (m, 2H), 1.7 (m, 2H), 1.9 (t, 2H), 2.1 (m, 4H), 2.3 (m, 1H), 2.7 (m, 2H), 3.1 (s, 3H), 3.4 (m, 1H), 3.95 (m, 1H), 7.1 (m, 2H), 7.3 (m, 8H); MS: 339. [0366]
  • Method AZ [0367]
  • 4-(2-Fluoroethylamino)-1-(3,3-diphenylpropyl)piperidine [0368]
  • This was prepared using a method similar to that used for 4-ethylamino-1-(3,3-diphenylpropyl)piperidine; MS: 341. [0369]
  • Method BA [0370]
  • 4-Chlorosulfonylphenylacetic acid. [0371]
  • Chlorosulfonic acid (10 ml, 148 mmol) was heated to 40° C. and phenyl acetic acid (5 g, 36.7 mmol) was added slowly. Stirred for two hours then cooled and carefully poured onto ice (50 g). The filtrate was cooled by filtration and dried under vacuum to afford the title compound as a pale cream solid. (7.9 g, 92%); NMR (CDCl[0372] 3), 3.80 (2H, s), 7.68 (2H, d), 8.00 (2H, d); MS: ES−233, ES+189.
  • Method BB [0373]
  • 4-Fluorosulfonylphenylacetic acid. [0374]
  • 18-Crown-6 (63 mg, 1 mol%) was added to a solution of 4-chlorosulfonylphenylacetic acid (5 g, 24 mmol) and KF (2.78 g, 48 mmol) in MeCN (5 mL) and stirred for 4 h. The product was then drowned out by the addition of water (100 mL) and collected by filtration to afford desired product (4.78 g, 97%); NMR (CDCl[0375] 3): 3.80 (2H, s), 7.68 (2H, d), 8.00 (2H, d); MS: 187.
  • Method BC [0376]
  • N-[1-(3,3-Diphenylpropyl)-4-piperidinyl]-N-methyl-4-fluorosulfonylphenylacetamide [0377]
    Figure US20040006081A1-20040108-C00028
  • To a solution of HATU (836 mg, 2.2 mmol), 4-fluorosulfonylphenylacetic acid (409 mg, 2.2 mmol), 1-(3,3-diphenylpropyl)-4-methylaminopiperidine (618 mg, 2 mmol) in DMF (10 mL) was added DIPEA (0.4 mL) and stirred over night. Poured onto water and extracted into ethyl acetate (50 mL). Washed (brine 100 mL) and dried over MgSO[0378] 4, and evaporated to afford a pale yellow solid. Trituration with ethyl acetate/hexane (50:50) afforded the title product as a pale yellow solid (577 mg, 57%); NMR: 1.80 (2H, m), 2.00 (2H, m), 2.40 (2H, m), 2.80-3.20 (6H, m), 3.27 (3H, s), 3.45 (2H, m), 3.92 (1H, m), 4.46 (1H, m) 7.27 (8H, m), 7.60 (2H, t), 8.04 (2H, d); MS: 509.
  • Method BD [0379]
  • N-[1-(3,3-diphenylpropyl)-4-piperidinyl]-N-methyl-4-methoxycarbonylphenylacetamide [0380]
    Figure US20040006081A1-20040108-C00029
  • Solid HATU (2.55 g; 6.7 mmol) followed by DIPEA (1.22 ml; 6.7 mmol) was added at room temperature to a solution of 4-methoxycarbonylphenylacetic acid (1.3 g; 6.7 mmol) in DMF (10 ml). After 5 minutes, 4-methylamino-1-(3,3-diphenylpropyl)piperidine (2.1 g; 6.7 mmol) was added and stirring continued overnight at ambient temp. The mixture was then partitioned between water (10 ml) and ethyl acetate (10 ml). The organic layer was separated, washed with water (1 ml) and dried over Na[0381] 2SO4 and evaporated to give an oil. Purification was by Bond Elut, eluting with a stepped gradient from DCM to 5% methanol in DCM yielding the title compound (2.47 g, 77%); MS: 485 (MH+).
  • Method BE [0382]
  • 4-tert-Butoxycarbonylamino-1-(3-R-phenyl-1-butanoic amide)piperidine [0383]
    Figure US20040006081A1-20040108-C00030
  • To a solution of 4-Boc-amino piperidine (2.46 g, 12.3 mmol) in DMF (30 mL) was added HATU (4.67 g, 12.3 mmol) and 3-R-phenyl-1-butanoic acid(2 g, 12.2 mmol) and DIPEA (2.12 mL). Stirred over night then poured into water and extracted into ethyl acetate. The organic extracts were dried over MgSO[0384] 4 and evaporated to afford the title compound as a white solid, (4.03 g, 94%); NMR: 1.20 (6H, m), 1.38 (9H, s), 1.65 (2H, m), 2.60 (2H, m), 3.00 (1H, m), 3.15 (1H, q), 3.40 (1H, m), 3.80 (1H, d, broad), 4.20 (1H, m), 6.80 (1H, m), 7.18 (1H, m), 7.24 (4H, m) MS: 347, 291 (−BOC).
  • Method BF [0385]
  • 4-Amino-1-(3-R-phenyl-1-butanoic amide)piperidine hydrochloride [0386]
    Figure US20040006081A1-20040108-C00031
  • To a solution of acetyl chloride (5 mL) in methanol (20 mL) was 4-Boc-amino-1-(3-R-phenyl-1-butanoic amide)piperidine (1 g, 3 mmol) and stirred for one hour. The solvents were then evaporated to afford the title compound as a white solid. (929 mg, 100% for HCl salt); NMR: 1.20 (3H, d), 1.35 (2H, m), 1.41 (1H, m), 1.89 (2H, m), 2.80-3.20 (5H, m), 3.90 (1H, d), 4.30 (1H, d), 7.10 (1H, m), 7.20 (4H, m); MS: 247. [0387]
  • Method BG [0388]
  • 4-Amino-1-(3-R-phenylbutyl)piperidine [0389]
    Figure US20040006081A1-20040108-C00032
  • To a solution of 4-amino-1-(3-R-phenyl-1-butanoic amide)piperidine(1 g, 3 mmol) in THF (20 mL) was added a solution of LiAlH[0390] 4 in THF (10 mL of 1.0M solution) and the mixture was refluxed for 5 hours. The mixture was cooled, quenched with aqueous sodium hydroxide, filtered and the filtrate partitioned between water and ethyl acetate. The combined organic phase was dried, MgSO4, and evaporated to afford the title compound as a white solid. (610 mg, 87%); NMR: 1.20 (4H, m), 1.60 (4H, m), 1.89 (2H, m), 2.10 (2H, m), 2.43 (1H, m), 2.70 (4H, m), 7.10 (3H, m), 7.20 (2H, m); MS: 233.
  • Method BH [0391]
  • 4-tert-Butoxycarbonylamino-1-(3-S-phenyl-1-butanoic amide)piperidine [0392]
    Figure US20040006081A1-20040108-C00033
  • To a solution of 4-Boc-amino piperidine (2.46 g, 12.3 mmol) in DMF (30 mL) was added HATU (4.67 g, 12.3 mmol) and 3-S-phenyl-1-butanoic acid (2 g, 12.2 mmol) and DIPEA (2.12 mL). Stirred over night then poured into water and extracted into ethyl acetate. Dried over MgSO[0393] 4 and evaporated to afford the title compound as a white solid, (4.17 g, 99%); NMR: 1.20 (6H, m), 1.38 (9H, s), 1.65 (2H, m), 2.60 (2H, m), 3.00 (1H, m), 3.15 (1H, q), 3.40 (1H, m), 3.80 (1H, d, broad), 4.20 (1H, m), 6.80 (1H, m), 7.18 (1H, m), 7.24 (4H, m); MS: 347, 291 (−BOC).
  • Method BI [0394]
  • 4-Amino-1-(3-S-phenyl-1-butanoic amide)piperidine hydrochloride [0395]
    Figure US20040006081A1-20040108-C00034
  • To a solution of acetyl chloride (5 mL) in methanol (20 mL) was added 4-Boc-amino-1-(3-S-phenyl-1-butanoic amide)piperidine(1 g, 3 mmol) and stirred for one hour. The solvents were then evaporated to afford the title compound as a white solid. (930 mg, 100% for HCl salt); NMR: 1.20 (3H, d), 1.35 (2H, m), 1. 41 (1H, m), 1.89 (2H, m), 2.80-3.20 (5H, m), 3.90 (1H, d), 4.30 (1H, d), 7.10 (1H, m), 7.20 (4H, m); MS: 247. [0396]
  • Method BJ [0397]
  • 4-Amino-1-(3-S-phenylbutyl)piperidine [0398]
    Figure US20040006081A1-20040108-C00035
  • To a solution of 4-amino-1-(3-S-phenyl-1-butanoic amide)piperidine(1 g, 3 mmol) in THF (20 mL) was added a solution of LiAlH[0399] 4 in THF (10 mL of 1.0M soln) and the mixture was refluxed for 5 hours. The mixture was cooled, quenched with aqueous sodium hydroxide, filtered and the filtrate partitioned between water and ethyl acetate. The combined organic phase was dried, MgSO4, and evaporated to afford the title compound as a white solid. (680 mg, 97%); NMR: 1.20 (4H, m), 1.60 (4H, m), 1.89 (2H, m), 2.10 (2H, m), 2.43 (1H, m), 2.70 (4H, m), 7.10 (3H, m), 7.20 (2H, m); MS: 233.
  • Method BK [0400]
  • N′-Phenylmethyl-N-(4-piperidinyl)-N-allylurea hydrochloride [0401]
    Figure US20040006081A1-20040108-C00036
  • Acetyl chloride (5.5 mL) was added to methanol (20 mL) at 0° C. and the mixture stirred for 10 minutes before addition of a solution of N′-phenylmethyl-N-(1-tert-butyloxycarbonyl-4-piperidinyl)-N-allylurea (1.54 g, 4.17 mmol) in methanol (1 mL). The resulting mixture was stirred at 0° C. for 1 h and at room temperature for 1 h. Evaporation afforded the title compound as a solid (0.96 g); NMR: 1.60 (br d, 2H), 1.93 (m, 2H), 2.80 (m, 22H), 3.10 (m, 2H), 3.79 (d, 2H), 4.21 (m, 3H), 5.10 (d, 1H), 5.18 (dd, 1H), 5.80 (ddt, 1H), 7.20 (m, 5H), 9.21 (br s, 2H); MS: 274. [0402]
  • Method BL [0403]
  • N′Phenylmethyl-N-(1-tert-butoxycarbonyl-4-piperidinyl)-N-allylurea [0404]
    Figure US20040006081A1-20040108-C00037
  • To a stirred solution of 1-tert-butoxycarbonyl-4-allylaminopiperidine (1.0 g, 4.17 mmol) in DCM (20 mL) was added benzylisocyanate (0.52 mL, 4.2 mmol) and the resulting mixture was stirred at room temperature for 20 h. Water was added and the mixture evaporated to yield the title compound (1.54 g, 99%); NMR 1.39 (s, 9H), 1.50 (m, 4H), 2.70 (m, 2H), 3.79 (d, 2H), 4.0 (mn, 3H), 4.21 (d, 2H), 5.10 (d, 1H), 5.18 (dd, 1H), 5.90 (ddt, 1H), 6.62 (t, 1), 7.20 (m, 5H); MS: 274 (MH[0405] +−BOC).
  • Method BM [0406]
  • 1-tert-Butoxycarbonyl-4-allylaminopiperidine [0407]
    Figure US20040006081A1-20040108-C00038
  • To a solution of 1-tert-butoxycarbonyl-4-piperidone (10.0 g, 50 mmol) in 1,2-dichloroethane (140 mL) was added allylamine (3.4 g, 60 mmol), acetic acid (3.0 mL) and 3 Å molecular sieves (20 g). The resulting mixture was stirred at room temperature for 45 min. Sodium triacetoxyborohydride (16.2 g, 76 mmol) was added and stirring was continued for a further 4 h. The reaction was quenched with water and extracted twice with ethyl acetate. The organic extracts were washed with sodium bicarbonate solution, combined, dried (MgSO[0408] 4) and concentrated to afford the title compound as an oil (11.5 g, 96%); NMR (CDCl3): 1.21 (m, 2H), 1.40 (s, 9H), 1.60 (br s, 1H), 1.81 (d, 2H), 2.63 (m, 1H), 2.80 (t, 2H), 3.29 (t, 2H), 4.05 (d, 2H), 5.10 (d, 1H), 5.18 (dd, 1H), 5.90 (ddt, 1H).
  • Method BN [0409]
  • N-(1-Phenylmethyl-4-piperidinyl-N-ethyl-4-fluorophenylacetamide [0410]
    Figure US20040006081A1-20040108-C00039
  • This was prepared by reacting 1-phenylmethyl-4-ethylaminopiperidine dihydrochloride with 4-fluorophenylacetic acid according to the procedure used for Method AJ; NMR (CDCl3): 1.13 and 1.19 (t, 3H), 1.35 and 1.85 (m, 2H), 1.74 and 2.08 (m, 2H), 2.90 (br m, 2H), 3.30 (m, 2H), 3.46 (s, 2H), 3.66 (s, 2H), 3.55 and 4.42 (m, 1H), 7.00 (m, 2H), 7.2-7.3 (m, 7H); MS: 355. [0411]
  • Method BO [0412]
  • N-[1-(3-phenyl]-3-oxopropyl)-4-piperidinyl]-N-ethyl-4-methanesulfonylphenylacetamide hydrochloride [0413]
    Figure US20040006081A1-20040108-C00040
  • To a solution of N-(4-piperidinyl)-N-ethyl-4-methanesulfonylphenylacetamide (Method AI) (14.8 g, 45.8 mmol) and DIPEA (24mL, 137 mmol) in DMF (250 mL) was added 3-chloropropiophenone (7.3 g, 43.5 mmol). The resulting mixture was stirred at room temperature for 20 h. The mixture was evaporated and the residue triturated with 5% MeOH/EtOAc to give a solid which was collected by filtration and washed with EtOAc affording the title compound (16.9 g, 75%); NMR (DMSO at 373K): 1.14 (t, 3H), 1.77 (m, 2H), 2.34 (m, 2H), 3.11 (m, 2H), 3.15 (s, 3H), 3.45-3.60 (m, 6H), 3.65 (t, 2H), 3.93 (s, 2H), 4.25 (br m, 1H), 7.53 (m, 4H), 7.65 (m, 1H), 7.84 (d, 2H) and 7.98 (d, 2H); MS: 457. [0414]
  • Method BP [0415]
  • 3-(3-Trifluoromethylphenyl)butyraldehyde [0416]
  • Step 1: (E)-Ethyl 3-(3-trifluoromethylphenyl)-2-butenoate [0417]
  • To a solution of triethyl phophonoacetate (1.98 ml, 10 mmol) in THF at 0° C. was added lithium bis(trimethylsilyl)amide (12 ml 1M in THF, 12 mmol) and the resulting mixture stirred. for 10 min. 3′-Trifluoromethylacetophenone (1.52 ml, 10 mmol) was added and the resulting mixture was stirred whilst allowing to warm to room temperature over 1 h. The mixture was evaporated and the residue partitioned between water and ethyl acetate, the organic phase was washed with brine, dried (MgSO[0418] 4) and evaporated. The residue was purified by Bond Elut chromatography (eluent isohexane then 1:1 ethyl acetate/isohexane) affording the sub-titled compound (1.4 g); NMR (CDCl3): 1.3 (t, 3H), 2.6 (s, 3H), 4.2 (q, 2H), 6.15 (s, 1H), 7.15 (m, 1H), 7.6 (m, 2H), 7.7 (s, 1H).
  • Step 2: Ethyl 3-(3-trifluoromethylphenyl)butanoate [0419]
  • To a solution of (E)-ethyl 3-(3-trifluoromethylphenyl)-2-butenoate (Step 1) (1.4 g) in ethyl acetate (50 ml) was added 10% Pd/C (140 mg) and the resulting mixture was stirred under an atmosphere of hydrogen for 18 h. The mixture was filtered through Celite® and the filtrate evaporated to give the sub-titled compound (1.33 g); NMR (CDCl[0420] 3): 1.2 (t, 3H), 1.35 (d, 3H), 2.6 (m, 2H), 3.4 (m, 1H), 4.1 (q, 2H), 7.4 (m, 4H).
  • Step 3: 3-(3-Trifluoromethylphenyl)butanol [0421]
  • To a solution of ethyl 3-(3-trifluoromethylphenyl)butanoate (Step 2) (1.35 g, 5.2 mmol) in THF (15 ml) at 0° C. was added lithium aluminium hydride (5.2 ml, 1M in THF, 5.2 mmol) and the resulting mixture was stirred for 5 min. Ethyl acetate (10 mL) was added followed by water (0.2 ml) then 6M NaOH solution (0.2 ml) then water (2 ml) and the resulting mixture stirred at room temperature for 5 min. before filtration through Celite®. The filtrate was dried (MgSO[0422] 4) and evaporated giving the sub-titled compound (1.1 g); NMR (CDCl3): 1.3 (d, 3H), 1.9 (m, 2H), 3.0 (m, 1H), 3.6 (m, 2H), 7.4 (m, 4H).
  • Step 4: 3-(3-Trifluoromethylphenyl)butyraldehyde [0423]
  • To a stirred solution of 3-(3-trifluoromethylphenyl)butanol (Step 3) (1.1 g, 5.05 mmol) in DCM (10 mL) was added Dess-Martin periodinane (2.36 g, 5.56 mmol) and the resulting mixture stirred at room temperature for 10 min. The mixture was washed three times with 2M NaOH solution (20 ml), then with brine (20 ml), dried (MgSO[0424] 4) and evaporated giving the title compound (1 g, 92%); NMR (CDCl3): 1.34 (d, 3H), 2.75 (m, 2H), 3.43 (m, 1H), 7.46 (m, 4H), 9.73 (s, 1H).
  • The same sequence of reactions was used to prepare 3-(3-chlorophenyl)butyraldehyde and 3-(3,4-dichlorophenyl)butyraldehyde except that platinum (IV) oxide was used as catalyst in the reduction of (E)-ethyl 3-(3-chlorophenyl)-2-butenoate and (E)-ethyl 3-(3,4-dichlorophenyl)-2-butenoate to ethyl 3-(3-chlorophenyl)butanoate and ethyl 3-(3,4-dichlorophenyl)butanoate respectively. [0425]
  • Method BQ [0426]
  • 3-Amino-1-(3,3-diphenylpropyl)pyrrolidine di-(trifluoroacetic acid) salt [0427]
  • Step 1: 3-Boc-amino-1-(3,3-diphenylpropyl)pyrrolidine [0428]
  • To a mixture of 3-boc-aminopyrrolidine (1 g, 5.4 mmol) and 3,3-diphenylpropionaldehyde (1.1 g, 5.4 mmol) in DCM (20 ml) and MeOH (5 ml) was added acetic acid (0.1 ml) and the resulting mixture stirred at room temperature for 1 h. Sodium triacetoxyborohydride (5.4 mmol) was added and the mixture stirred for 18 h. The reaction mixture was washed twice with water (10 ml), dried and evaporated giving the sub-titled compound (2.1 g); MS: 381. [0429]
  • Step 2: 3-Amino-1-(3,3-diphenylpropyl)pyrrolidine di-(trifluoroacetic acid) salt [0430]
  • 3-Boc-amino-1-(3,3-diphenylpropyl)pyrrolidine (Step 1) (2.1 g) was dissolved in trifluoroacetic acid (10 mL) and the resulting mixture was stirred at room temperature for 2 h then evaporated giving the title compound (2.3 g). [0431]
  • Method BR [0432]
  • 3-(4-Chlorophenyl)-3-(4-pyridyl)propionaldehyde [0433]
  • Step 1: 3-(4-Chlorophenyl)-3-(4-pyridyl)prop-1-ene [0434]
  • To a solution of 4-(4-chlorobenzyl)pyridine (1 g, 4.9 mmol) in THF was added n-butyl lithium (3.4 ml of 1.6M solution, 5.4 mmol) dropwise at room temperature. After stirring for 15 min. the mixture was cooled to −78° C. and allyl bromide (0.65 g, 5.4 mmol) was added dropwise. The reaction mixture was stirred while warming to room temperature over 18 h. The mixture was purified by Bond Elut chromatography (eluent isohexane then diethyl ether) giving the sub-titled compound as an oil (0.54 g); NMR (CDCl[0435] 3): 2.8 (t, 2H), 4.0 (t, 1H), 5.0 (m, 2H), 5.7 (m, 1H), 7.1 (m, 4H), 7.3 (m, 2H) and 8.5 (m, 2H); MS: 244.
  • Step 2: 3-(4-Chlorophenyl)-3-(4-pyridyl)propionaldehyde [0436]
  • 3-(4-Chlorophenyl)-3-(4-pyridyl)prop-1-ene (Step 1) (0.54 g, 2.2 mmol) was dissolved in MeOH (30 ml) and the solution cooled to −78° C. Ozone was bubbled through until a blue colour persisted (20 min.). The mixture was purged with oxygen and dimethyl sulphide (0.33 ml) was added. The mixture was stirred for 1 h while warming to room temperature, then evaporated and the crude product used directly in the next reaction. [0437]
  • The same sequence of two reactions was used to prepare 3-(4-chlorophenyl)-3-(2-pyridyl)propionaldehyde. [0438]
  • Method BS [0439]
  • 3-(1,3-Benzodioxol-5-yl)-3-phenylpropionaldehyde [0440]
  • Step 1: (E)-tert-Butyl 3-(1,3-benzodioxol-5-yl)propenonate [0441]
  • A solution of 3,4-methylenedioxycinnamic acid (0.77 g, 4 mmol) in toluene (10 ml) was heated with stirring to 80° C. and N,N-dimethylformamide di-tert-butyl acetal (3.83 ml, 16 mmol) was added dropwise. The resulting mixture was stirred at 80° C. for 2 h then cooled to room temperature. The mixture was washed with water and brine, dried (Na[0442] 2SO4) and evaporated. The residue was purified by Bond Elut chromatography (eluent iso-hexane then DCM) giving the sub-titled compound as a solid (0.48 g).
  • Step 2: tert-Butyl 3-(1,3-benzodioxol-5-yl)-3-phenylpropionate [0443]
  • To a −78° C. solution of (E)-tert-butyl 3-(1,3-benzodioxol-5-yl)propenonate (Step 1) (2.4 mmol) in THF (5 ml) was added phenyl lithium (2 ml of 1.8M solution, 3.6 mmol) dropwise and the resulting mixture stirred at −78° C. for 2 h. Water (5 ml) was added and the mixture allowed to warm to room temperature over 18 h. The mixture was extracted with ethyl acetate, the organic phase was concentrated and the residue purified by Bond Elut chromatography (eluent iso-hexane then DCM) giving the sub-titled compound as an oil (0.51 g). [0444]
  • Step 3: 3-(1,3-Benzodioxol-5-yl)-3-phenylpropionaldehyde [0445]
  • To a −78° C. solution of tert-butyl 3-(1,3-benzodioxol-5-yl)-3-phenylpropionate (Step 2) (1.36 mmol) in DCM (5 ml) was added diisobutylaluminium hydride (3 ml 1M solution, 3 mmol) dropwise and the resulting mixture stirred at −78° C. for 90 min. MeOH (3 ml) was added slowly and the mixture warmed to room temperature. Citric acid solution (10% aqueous, 5 ml) was added, the mixture stirred for 10 min. then filtered. The filtrate was dried and evaporated yielding the title compound which was used immediately in the next reaction. [0446]
  • The same sequence of three reactions was used to prepare 3-(4-chlorophenyl)-3-phenylpropionaldehyde, 3-(3,4-dichlorophenyl)-3-phenylpropionaldehyde, 3-(4-methoxyphenyl)-3-phenylpropionaldehyde, 3-(3-chlorophenyl)-3-phenylpropionaldehyde, 3-(4-methylphenyl)-3-phenylpropionaldehyde and 3-(4-trifluoromethylphenyl)-3-phenylpropionaldehyde. [0447]
    • EXAMPLE 34
  • The ability of compounds to inhibit the binding of RANTES was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0.1 nM iodinated RANTES, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated RANTES bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated RANTES was calculated (IC[0448] 50). Preferred compounds of formula (I) have an IC50 of less than 50 μM.
    • EXAMPLE 35
  • The ability of compounds to inhibit the binding of MIP-1α was assessed by an in vitro radioligand binding assay. Membranes were prepared from Chinese hamster ovary cells which expressed the recombinant human CCR5 receptor. These membranes were incubated with 0.1 nM iodinated MIP-1α, scintillation proximity beads and various concentrations of the compounds of the invention in 96-well plates. The amount of iodinated MlP-1α bound to the receptor was determined by scintillation counting. Competition curves were obtained for compounds and the concentration of compound which displaced 50% of bound iodinated MIP-1α was calculated (IC[0449] 50). Preferred compounds of formula (I) have an IC50 of less than 50 μM.
    Figure US20040006081A1-20040108-C00041
    Figure US20040006081A1-20040108-C00042
    Figure US20040006081A1-20040108-C00043
    Figure US20040006081A1-20040108-C00044
    Figure US20040006081A1-20040108-C00045
    Figure US20040006081A1-20040108-C00046
    Figure US20040006081A1-20040108-C00047
    Figure US20040006081A1-20040108-C00048
    Figure US20040006081A1-20040108-C00049
    Figure US20040006081A1-20040108-C00050
    Figure US20040006081A1-20040108-C00051
    Figure US20040006081A1-20040108-C00052
    Figure US20040006081A1-20040108-C00053
    Figure US20040006081A1-20040108-C00054
    Figure US20040006081A1-20040108-C00055
    Figure US20040006081A1-20040108-C00056
    Figure US20040006081A1-20040108-C00057
    Figure US20040006081A1-20040108-C00058
    Figure US20040006081A1-20040108-C00059
    Figure US20040006081A1-20040108-C00060
    Figure US20040006081A1-20040108-C00061
    Figure US20040006081A1-20040108-C00062
    Figure US20040006081A1-20040108-C00063

Claims (16)

1. A compound of formula (I):
Figure US20040006081A1-20040108-C00064
wherein:
R1 is C1-6 alkyl, C3-7 cycloalkyl, C3-8 alkenyl or C3-8 alkynyl, each optionally substituted with one or more of: halo, hydroxy, cyano, nitro, C3-7 cycloalkyl, NR8R9, C(O)R10, NR13C(O)R14, C(O)NR17R18, NR19C(O)NR20R21, S(O)nR22, C1-6 alkoxy (itself optionally substituted by heterocyclyl or C(O)NR23R24), heterocyclyl, heterocyclyloxy, aryl, aryloxy, heteroaryl or heteroaryloxy;
R2 is hydrogen, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
R3 is C1-8 alkyl, C2-8 alkenyl, NR45R46, C2-8 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
R46 is C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl, heterocyclyl, aryl(C1-4)alkyl, heteroaryl(C1-4)alkyl or heterocyclyl(C1-4)alkyl;
wherein the groups of R2, R3 and R46, and the heterocyclyl, aryl and heteroaryl moieties of R1, are independently optionally substituted by one or more of halo, cyano, nitro, hydroxy, S(O)qR25, OC(O)NR26R27, NR28R29, NR30C(O)R31, NR32C(O)NR33R34, S(O)2NR35R36, NR37S(O)2R38, C(O)NR39R40, C(O)R41, CO2R42, NR43CO2R44, C1-6 alkyl, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; the C3-7 cycloalkyl, aryl, heteroaryl and heterocyclyl moieties of R1, R2 and R3 being additionally optionally substituted with C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl or C1-6 alkoxy(C1-6)alkyl;
R4, R5, R6 and R7 are, independently, hydrogen, C1-6 alkyl {optionally substituted by halo, cyano, hydroxy, C1-4 alkoxy, OCF3, NH2, NH(C1-4 alkyl), N(C1-4 alkyl)2, NHC(O)(C1-4 alkyl), N(C1-4 alkyl)C(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), N(C1-4 alkyl)S(O)2(C1-4 alkyl), CO2(C1-4 alkyl), C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, C(O)NH2, CO2H, S(O)2(C1-4 alkyl), S(O)2NH(C1-4 alkyl), S(O)2N(C1-4 alkyl)2, heterocyclyl or C(O)(heterocyclyl)}, S(O)2NH2, S(O)2NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2, C(O)(C1-4 alkyl), CO2H, CO2(C1-4 alkyl) or C(O)(heterocyclyl); or two of R4, R5, R6 and R7 can join to form, together with the ring to which they are attached, a bicyclic ring system; or two of R4, R5, R6 and R7 can form an endocyclic bond (thereby resulting in an unsaturated ring system);
X is C(O), S(O)2, C(O)C(O), a direct bond or C(O)C(O)NR47;
k, m, n, p and q are, independently, 0, 1 or 2;
R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 and R44 are, independently, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, C3-7 cycloalkyl, aryl, heteroaryl or heterocyclyl each or which is optionally substituted by halo, cyano, nitro, hydroxy, C1-4 alkyl, C4 alkoxy, SCH3, S(O)CH3, S(O)2CH3, NH2, NHCH3, N(CH3)2, NHC(O)NH2, C(O)NH2, NHC(O)CH3, S(O)2N(CH3)2, S(O)2NHCH3, CF3, CHF2, CH2F, CH2CF3 or OCF3; and R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 and R44 may additionally be hydrogen;
R8, R9, R10, R13, R14, R17, R18, R19, R20, R21, R23, R24, R45 and R47 are, independently, hydrogen, alkyl {optionally substituted by halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy)}, phenyl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3) or heteroaryl (itself optionally substituted by halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3);
R22 is alkyl {optionally substituted by halo, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, heterocyclyl or phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy)}, phenyl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy) or heteroaryl (itself optionally substituted by halo, hydroxy, cyano, C1-4 alkyl or C1-4 alkoxy);
the pairs of substituents: R8 and R9, R13 and R14, R17 and R18, R20 and R21, R23 and R24, R26 and R27, R28 and R29, R30 and R31, R32 with either R33 or R34, R33 and R34, R35 and R36, R37 and R38, R39 and R40 and R43 and R44 may, independently, join to form a ring and such a ring may also comprise an oxygen, sulphur or nitrogen atom;
where for any of the foregoing heterocyclic groups having a ring —N(H)— moiety, that —N(H)— moiety may be optionally substituted by C1-4 alkyl (itself optionally substituted by hydroxy), C(O)(C1-4 alkyl), C(O)NH(C1-4 alkyl), C(O)N(C1-4 alkyl)2 or S(O)2(C1-4 alkyl);
a ring nitrogen and/or sulphur atom is optionally oxidised to form an N-oxide and/or an S-oxide;
foregoing heteroaryl or heterocyclyl rings are C- or, where possible, N-linked;
or a pharmaceutically acceptable salt thereof or a solvate thereof.
2. A compound as claimed in claim 1 wherein heteroaryl is pyrrolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, thienyl, furyl, quinolinyl, isoquinolinyl, dihydroisoquinolinyl, indolyl, benzimidazolyl, benzo[b]furyl, benzo[b]thienyl, phthalazinyl, indanyl, oxadiazolyl or benzthiazolyl.
3. A compouind as claimed in claim 1 or 2 wherein aryl is phenyl.
4. A compound as claimed in claim 1, 2 or 3 wherein heterocyclyl is piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl or tetrahydrofuryl.
5. A compound as claimed in claim 1, 2, 3 or 4 wherein R4, R5, R6 and R7 are all hydrogen.
6. A compound as claimed in claim 1, 2, 3, 4, or 5 wherein X is C(O).
7. A compound as claimed in claim 1, 2, 3, 4, 5 or 6 wherein m and p are both 1.
8. A compound as claimed in claim 1, 2, 3, 4, 5, 6 or 7 wherein R2 is methyl, ethyl, allyl, cyclopropyl or propargyl.
9. A compound as claimed in claim 1, 2, 3, 4, 5, 6, 7 or 8 wherein R3 is NR45R46, aryl, heteroaryl, aryl(C1-4)alkyl or heteroaryl(C1-4)alkyl; R45 is hydrogen or C1-6 alkyl; R46 is aryl, heteroaryl, aryl(C1-4)alkyl or heteroaryl(C1-4)alkyl; wherein the aryl and heteroaryl groups of R3 and R46 are independently substituted by S(O)qR25, OC(O)NR26R27, NR32C(O)NR33R34 or C(O)R41, and optionally further substituted by one or more of halo, cyano, nitro, hydroxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy(C1-6)alkyl, S(O)qR25, OC(O)NR26R27, NR28R29, NR30C(O)R31, NR32C(O)NR33R34, S(O)2NR35R36, NR37S(O)2R38, C(O)NR39R40, C(O)R41, CO2R42, NR43CO2R44, C3-10 cycloalkyl, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, phenyl, phenyl(C1-4)alkyl, phenoxy, phenylthio, phenyl(C1-4)alkoxy, heteroaryl, heteroaryl(C1-4)alkyl, heteroaryloxy or heteroaryl(C1-4)alkoxy; wherein any of the immediately foregoing phenyl and heteroaryl moieties are optionally substituted with halo, hydroxy, nitro, S(O)kC1-4 alkyl, S(O)2NH2, cyano, C1-4 alkyl, C1-4 alkoxy, C(O)NH2, C(O)NH(C1-4 alkyl), CO2H, CO2(C1-4 alkyl), NHC(O)(C1-4 alkyl), NHS(O)2(C1-4 alkyl), C(O)(C1-4 alkyl), CF3 or OCF3; wherein q, k, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37, R38, R39, R40, R41, R42, R43 and R44 are as defined in claim 1.
10. A compound as claimed in claim 1, 2, 3, 4, 5, 6, 7, 8 or 9 wherein R1 is 2,6-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4-dimethoxy-6-hydroxybenzyl, 3-(4-dimethylamino-phenyl)prop-2-enyl, (1-phenyl-2,5-dimethylpyrrol-3-yl)methyl, 2-phenylethyl, 3-phenylpropyl, 3-R/S-phenylbutyl, 3-cyano-3,3-diphenylpropyl, 3-cyano-3-phenylpropyl, 4-(N-methylbenzamido)-3-phenylbutyl or 3,3-diphenylpropyl.
11. A pharmaceutical composition which comprises a compound of the formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.
12. A compound of the formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, for use as a medicament.
13. A compound of formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, in the manufacture of a medicament for use in therapy.
14. A compound of formula (I), or a pharmaceutically acceptable salt thereof or solvate thereof, in the manufacture of a medicament for use in modulating CCR5 receptor activity in a warm blooded animal.
15. A method of treating a patient comprising administering a compound of formula (I) as claimed in claim 1, or a pharmaceutically acceptable salt thereof or solvate thereof, or a composition as claimed in claim 11.
16. A process for the preparation of a compound of formula (I) as claimed in claim 1 comprising:
a. reductively aminating a compound of formula (II):
Figure US20040006081A1-20040108-C00065
with an aldehyde R3CHO; or
b. where R1 is optionally substituted alkyl, reacting a compound of formula (III):
Figure US20040006081A1-20040108-C00066
with an alkyl halide, in the presence of a base.
US10/276,430 2000-05-17 2001-05-14 Pharmaceutically active piperidine derivatives, in particular as modulators of chemokine receptor activity Abandoned US20040006081A1 (en)

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